Delivery systems for control of gastrointestinal bleeding

ABSTRACT

The present disclosure relates to a gastrointestinal delivery device of a dressing, where the delivery device is capable of fitting through a narrow channel before expanding and applying the dressing. The gastrointestinal delivery device may be used in all gastrointestinal bleeding applications and can be used with a biocompatible, foldable, thin profile, chitosan dressing. Various aspects of the device and its uses are provided herein.

GOVERNMENT LICENSE RIGHTS

This invention was made with Government support under R44DK104564awarded by National Institute of Diabetes and Digestive and KidneyDisease. The Government has certain rights in the invention.

BACKGROUND Technical Field

This disclosure relates to gastrointestinal medical devices and deliverysystems.

Description of the Related Art

Prolonged bleeding, with its associated risks in mortality andmorbidity, remains a serious problem in the gastrointestinal (GI) tract.Improved techniques, devices, and dressings that could provide for rapidbleeding control in gastrointestinal bleeding (GIB) for both uppergastrointestinal bleeding (UGIB) and lower gastrointestinal bleeding(LGIB) are needed.

Although there have been advances in bleeding control using advanceddressings for applications outside of GIB bleeding, none of theseadvances have yet translated to the unique conditions of thegastrointestinal tract and especially the upper gastrointestinal tractwhere delivery, adhesion, enzyme activity and acidity considerations arehighly challenging. Gastrointestinal bleeding (GIB) is a commonpresentation to the emergency department. According to the U.S.Department of Health & Human Service, from 2000 to 2014, there was anaverage of over 350,000 discharges from gastrointestinal hemorrhageannually. In the U.S., the direct hospital cost in 2010 due to GIBexceeded $1.1 billion [1]. Upper GIB (UGIB), defined as gastrointestinalbleeding proximal to the ligament of Treitz, is approximately five timesmore common than lower GIB (LGIB) [2]. Acute UGIB is a potentiallylife-threatening emergency that necessitates prompt assessment,resuscitation and appropriate medical and endoscopic management. Despiterecent advances in management of GIB in western countries, the mortalityrate of acute UGIB has not significantly improved, and remains as highas 10-14% [3, 4]. The major cause of death after GIB is death secondaryto cardiorespiratory complications, which is not surprising given theburden of comorbidities in such patients; death due to uncontrollablehemorrhage is reported to account for between 20% and 25% of cases [5,6]. While little can be done to correct comorbidities urgently, moreeffective and rapid bleeding control will allow significant reductionsin the incidence of UGIB related morbidity and mortality. In general,the most common causes of acute UGIB are peptic ulcers,gastro-esophageal varices, Mallory-Weiss tears and erosiveesophagogastritis [7]. Nonvariceal upper gastrointestinal bleeding(NVUGIB) encompasses all causes of UGIB except bleeding esophageal orgastric varices. The incidence of peptic ulcer disease has decreasedbecause of the development and utilization of proton pump inhibitors aswell as the identification, treatment and eradication of Helicobacterpylori in individual patients [8]. Despite decreased peptide ulcerincidence, mortality among NVUGIB patients ranges from 3-4% [9]. Whilerarely life threatening, gastric malignancies can lead to friable tissuewith diffuse bleeding that is difficult to address with traditionalphysical hemostatic methods (clips, bands, ligation) or cautery [10].

Current endoscopic management of patients with acute UGIB includesthermal therapy (e.g., bipolar electrocoagulation, heater probe,monopolar electrocoagulation, argon plasma coagulation, and laser),injection (epinephrine, sclerosants (e.g., absolute ethanol,polidocanol, and ethanolamine), thrombin or fibrin glue (thrombin plusfibrinogen)), and clips [11, 12]. Conventional clips and bands aregenerally steel or rubber closure systems that require accurateplacement and stop or slow bleeding by compressing bleeding bloodvessel(s) closed.

In general, the majority of patients with bleeding peptic ulcers,hemostasis is achieved with combination of the above endoscopictherapeutic modalities. However, there remains a subset of patients,approximately 5%, in which endoscopic treatments are not sufficient forhemostasis and thus require interventional radiology or surgicalinterventions [13, 14].

Endoscopic therapy fails for a variety of reasons including poorvisibility of lesion due to active pulsating bleeding, difficultanatomic location of lesion for endoscopy, maximal therapy withcurrently available tools, and severe coagulopathy.

Only available outside the United States, three different spray-based,hemostatic powder devices, Ankeford Blood Stopper [15], EndoClot™ [16]and HemoSpray™ [17-19] are also being considered to control NVUGIB. Apotential concern with Hemospray® is that it is a related product toWoundStat™ which was withdrawn in 2009 in the U.S. due to promotion ofdiffuse micro-emboli [20] that could cause tissue necrosis and organfailure. Hemospray is generally delivered as an aspirated suspendedpowder of about 10 g of loose powder into a cavity and takes about 5minutes after application to achieve satisfactory control (e.g., apurported success rate of about 85%) of Forrest 1a hemorrhage. Althoughexisting tools in the U.S. readily control a significant portion ofUGIB, there remains unmet need for the control of brisk arterialbleeding that results in significant mortality and health careexpenditure. The devices described herein, for the first time comprisedelivery of a hemostatic dressing by, for example, a wire deliverydevice, for control of GI bleeding, including, particularly, UGIB. Thedevices described herein, however, represent a substantial improvementin the art for closure of brisk bleeding sites (hemorrhagic), e.g.,Forrest 1a bleeding rates at about 25 ml/min or about 20 ml/min, whichcurrent technologies do not readily address. Further, the devicesdescribed herein may include dressings comprising chitosan that cancontrol hemorrhage in anticoagulated subjects.

BRIEF SUMMARY

The gastrointestinal hemostatic dressing devices described herein areamenable to use in all gastrointestinal bleeding applications and can beused to deliver and apply a dressing to a target tissue site via anarrow channel such as, for example, an endoscopic channel. The devicesdescribed herein may be used in minimally invasive procedures. Thedevices described herein comprise an axis, an expandable support, adressing and, optionally, a sheath. In some embodiments, a singlestructure may serve as both the axis and the expandable support. Forexample, the device may comprise a wire base axis, a balloon catheterexpandable support, and a dressing delivered through a standardendoscopic working channel having a diameter of less than or equal to3.2 mm, or a laser-cut cylinder of nitinol or stainless steel with freeends.

The devices provide for the compact delivery of a splayed high surfacearea dressing to a target tissue treatment site. In a preferredembodiment, the hemostatic dressing is a chitosan gastrointestinalhemostatic dressing (CGHD). In another preferred embodiment, eachdressing weighing, for example, about 0.025 g, when in contact with (orapplied directly over) the target tissue site, adheres to the targettissue site in about 30 seconds and may be used to control a Forrest 1ahemorrhage upon serial application of 1 to 3 dressings, i.e., within 30seconds to 3 minutes.

UGIB bleed rates, or blood flow rates, in ml/min suitable for treatmentby the devices described herein may range from about 1 ml/min to about200 ml/min. In preferred embodiments, the bleeding rates addressed bythe devices range from about 1 ml/min to about 150 ml/min. A Forrest 1aUGIB is about 25 ml/min. For subjects suffering a bleed rate of muchgreater than a Forrest 1a, survival is problematic unless they arealready in an operating theater. UGIB bleed rate of between about 20ml/min and 25 ml/min is considered “brisk” bleeding. Oozing bleeding isgenerally greater than about 1 ml/min as it is noted that low bleedingrates such as 1 ml/min typically clot and stop of their own accordunless the subject is on anticoagulation therapy or has a disorder ofthe clotting cascade due to reasons other than taking anticoagulationmedication. For such a subject with irreversible anticoagulationmedication or with a bleeding disorder, 1 ml/min oozing bleeding remainsconcerning and needs to be addressed such as by the device of theinvention. In some embodiments, the devices described herein are used toaddress UGIB bleeding rates of between about 1 ml/min and about 25ml/min, or about 1 ml/min and about 20 ml/min, or about 1 ml/min andabout 15 ml/min, or about 1 ml/min and about 10 ml/min, or about 1ml/min and about 5 ml/min.

The devices disclosed herein provide new treatment approaches involvinga dressing material and an opportunity to address or mitigatedeficiencies with current modalities, such as clipping, thermalcoagulation and injection for treatment of gastrointestinal (GI)bleeding, which necessitate pinpoint accuracy and which are challengingunder impaired visibility of brisk, e.g., (Forrest 1a), bleedingconditions.

Further, the devices disclosed herein provide a therapeutic option thatpromotes or provides hemostasis in a way that allows the body to betterheal itself and without inflicting further physical damage to a targettissue site, such as can occur with clipping or thermal coagulation.

In one embodiment, the gastrointestinal delivery devices describedherein comprise: an expandable support and a releasable dressing, andthe device is capable of fitting through a channel of 4 mm diameter orless. In some embodiments, the device is capable of fitting through oneof: a channel of 3.8 mm diameter or less; a channel of 3.5 mm or less;or a channel of 3.2 mm or less. In some embodiments, the releasabledressing attaches to the expandable support. In some embodiments, thedevice further comprises a sheath that envelopes the expandable supportand the dressing. In some embodiments, the sheath constrains anexpansion tension from the expandable support. In some embodiments, theexpandable support is in an expanded format configuration. In someembodiments, the device further comprises an axis connected to theexpandable support. In some embodiments, the expandable supportcomprises an annular shape in an expanded format configuration. In someembodiments, the expandable support comprises a ribbon spring annulardressing support. In some embodiments, the expandable support comprisesmore than one wire. In some embodiments, the expandable supportcomprises a stable balloon in an expanded format configuration. In someembodiments, the expandable support comprises an umbrella style wireframe. In some embodiments, the expandable support comprises at leasttwo articulated spring arms connecting to the releasable dressing. Insome embodiments, the expandable support comprises two or morearticulated base support spring struts, and the at least two articulatedspring arms may connect to both the axis and the base support springstruts. In some embodiments, the axis comprises a wire. In someembodiments, the axis comprises articulated spring arms. In someembodiments, at least one component of the device is selected from thegroup consisting of: a protective sheath, and an axis formed of ribbonspring wire. In some embodiments, the device further comprises a springlocator positioning arm, wherein the spring locator positioning armcomprises a first end connecting to the axis and a second end connectingto the expandable support. In some embodiments, the axis is also theexpandable support. In some embodiments, the releasable dressing is achitosan dressing attached to the expandable support at a dressing tab,and the one or more dressing tabs are reinforced by at least one ofincreased dressing density, increased dressing thickness, and/or sewnfibers. In some embodiments, all components of the device other than thereleasable dressing consist of wires and, optionally, spring wires. Insome embodiments, all components of the device other than the releasabledressing consist of a single wire and, optionally, a spring wire.

In some embodiments, methods of delivering a releasable dressing in vivoto a target tissue site in the gastrointestinal tract using a devicedescribed herein, comprises: (a) fitting the expandable support, thereleasable dressing, and the axis into a narrow channel of 4 mm diameteror less; (b) expanding the expandable support at a target tissue site;(c) adhering the releasable dressing to the target tissue site; and (d)removing the expandable support and the axis from the target tissuesite.

In some embodiments, methods of treating gastrointestinal bleeding usingthe gastrointestinal delivery device described herein comprises: (a)fitting the expandable support, the releasable dressing, and the axisinto a narrow channel of 4 mm diameter or less; (b) expanding theexpandable support at a target tissue site; (c) adhering the releasabledressing to the target tissue site; and (d) stopping gastrointestinalbleeding. In some embodiments, the method further comprises applyinglight pressure on the releasable dressing at the target tissue site. Insome embodiments, the light pressure is about 200-300 g. In someembodiments, the light pressure is applied for about 10 to 60 seconds.In some embodiments, the methods further comprise stopping bleedingwherein blood flow rates are between about 1 ml/min to about 150 ml/min.In some embodiments, the methods further comprise providing a releasabledressing in a compact condition, and wherein the releasable dressingcomprises chitosan. In some embodiments, the narrow channel is a channelof a gastroscope. In some embodiments, the narrow channel is a deliveryport of a gastroscope. In some embodiments, the methods further comprisethe step of terminally sterilizing the device, wherein the releasabledressing is terminally sterilized.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 depicts a chemical structure representation of chitosan (R1=H andacetyl radical) and catechol modified chitosan (R1=H, acetyl,hydrocaffeic acid radical, caffeic acid radical, trans-caffeic acidradical and Homoprotocatechuic acid radical). For chitosan polymer,preferably n>60, more preferably n>300, and most preferably n>600.

FIG. 2 depicts an N-acylation addition reaction in the presence of1-ethyl-3-(-3-dimethylamino-propyl)-carbodiimide (EDC) where3,4-dihydroxyhydrocinnamic is covalently attached to a chitosan C-2amine with a degree of substitution of 25% in aqueous solution at pH5.5.

FIG. 3 depicts oxidation of catechol modified chitosan to ortho-quinonemodified chitosan under elevated pH and in the presence of oxygen

FIG. 4 depicts Schiff base (A) and Michael addition (B) reactionscausing crosslinking between catechol modified chitosan and chitosan.

FIG. 5 depicts round-shaped catechol modified chitosan dressing that are(pre-cut) 2.5 inch & 2 inch diameter compressed to near 50 microns. Thecoloration of these catechol modified chitosan dressing, starting fromleft to right, ranges from light pinkish brown (first dressing), 2dressings of darker pinkish brown, 2 tan brown colored dressings (nopink), 1 brown dressing and lastly 1 darker brown. Catechol chitosandressings 5 & 6 are formed from 2.5″ and 2″ molds and they are backedwith unmodified chitosan dressings both from 2.5″ molds and theunmodified chitosan can be seen clearly as the white halo (no brown orpink color) in dressing 6. The catechol chitosan and unmodified chitosandressings were adhered together during compression to a final shareddensity >0.4 g/cm3. The pink coloration is associated with unoxidizedcatechol while the brown color is associated with the oxidized catechol(o-quinone). The lighter browns and lighter pinks are associated withlower degree of substitution of the chitosan with catechol (nearer 10%)while the darker colorations (pinkish brown & brown) are associated withhigher degree of substitution of the chitosan with catechol (nearer to20%).

FIGS. 6A, 6B, and 6C depict a table showing different formulations ofdressing, dissolution testing results, foldability testing results &acute in vivo screen results of the different formulations.

FIG. 7 depicts a catechol modified chitosan dressing that has beenfolded and unfolded, remaining intact with visible fold axis (crease).

FIGS. 8A-8C depict a table showing formulation approaches, hydrophilicpolymers, and % w/w of solution hydrophilic polymer components.

FIG. 9 depicts a gastroscope digital image of the modified catecholchitosan dressing of the invention intimately adhered to stomach mucosa,demonstrating slight swelling in the stomach environment, andeffectively controlling upper gastrointestinal hemorrhage (Forrest 1a)of a lacerated gastroepiploic artery inside the stomach of a heparinized(ACT≥250 s) swine 3 hours after application of the dressing to thearterial injury.

FIG. 10 demonstrates the presence of a strong intact clot under thedressing of FIG. 9 at animal sacrifice which was within 45 minutes oftaking the image of FIG. 9 . The modified chitosan dressing was shown tobe uniformly adhered to the injury and stomach mucosa at sacrifice.

FIG. 11 a provides schematic drawings of portions of a delivery systemfor a dressing for controlling gastrointestinal bleeding, including wirecomponents thereof.

FIG. 11 b provides schematic drawings of portions of a delivery systemfor a dressing for controlling gastrointestinal bleeding, includingballoon components thereof.

FIG. 11 c provides schematic drawings of a delivery system for adressing for controlling gastrointestinal bleeding, including the wirecomponents illustrated in FIG. 11 a and the balloon components of FIG.11 b.

FIG. 12 a provides schematic drawings of another delivery system for adressing for controlling gastrointestinal bleeding, including ballooncomponents without the wire components of FIG. 11 a.

FIG. 12 b provides schematic drawings of another delivery system for adressing for controlling gastrointestinal bleeding, including anumbrella-like structure that can be expanded or collapsed to controldeployment of the dressing.

FIG. 13 a provides a schematic drawing of a side view of anotherdelivery system that includes a plurality of radially-spaced apart armsin an expanded format.

FIG. 13 b provides another schematic drawing of a side view of thedelivery system of FIG. 13 a in an unexpanded format.

FIG. 13 c provides a schematic drawing of an end view of the deliverysystem of FIGS. 13 a-13 b in the expanded format without a dressingcoupled thereto.

FIG. 13 d provides a schematic drawing of another end view of thedelivery system of FIGS. 13 a-13 c in the expanded format with adressing coupled thereto (normally the four attachment tabs (17) wouldbe hidden & folded back behind the front of the dressing to provideattachment to the delivery device. The tabs are shown here extended forcompleteness of the image of the dressing form).

FIG. 13 e provides a schematic drawing of another end view of thedelivery system of FIGS. 13 a-13 d in a partially expanded format with adressing coupled thereto, the dressing partially folded.

FIG. 13 f provides a schematic drawing of another end view of thedelivery system of FIGS. 13 a-13 e in an unexpanded format with adressing coupled thereto, the dressing folded and partially wrappedabout components of the delivery system.

FIG. 14 a provides a side view of another delivery system for a dressingfor controlling gastrointestinal bleeding.

FIG. 14 b provides an end view of the delivery system of FIG. 14 a.

FIG. 15 a provides a side view of another delivery system for a dressingfor controlling gastrointestinal bleeding.

FIG. 15 b provides an end view of the delivery system of FIG. 15 a.

Throughout this description it is to be understood that referenceidentifiers applied in relation to a specific figure feature also relateto like or similar features depicted in other figures regardless ofwhether such figure features are specifically called out in connectionwith each figure below.

DETAILED DESCRIPTION

This disclosure generally relates to gastrointestinal hemostaticdressing devices that can be used in all gastrointestinal bleedingapplications to deliver and apply a dressing to a target tissue site viaa narrow channel such as, for example, an endoscopic channel. Thedevices described herein comprise an axis, an expandable support, adressing and, optionally, a sheath. In some embodiments, a singlestructure may serve as both the axis and the expandable support. Thedevices provide for the compact delivery of a splayed high surface areadressing to a target tissue treatment site. Suitable dressing materialsinclude, for example, a chitosan gastrointestinal hemostatic dressing(CGHD). The devices described herein are capable of being used alone,i.e., without delivery assisted by passing through a narrow channel.Alternatively, the gastrointestinal delivery device provided herein canbe used in combination with other medical devices, including but notlimited to, an endoscope, such as an endoscope for gastroscopy. Thedevices described herein may be suitable for use with non-invasive orminimally-invasive medical procedures. The devices described hereinprovide a releasable dressing that is left in place at a target tissuesite while the remaining device components are removed after thereleasable dressing is adhered to a target tissue site.

The devices described herein are capable of being fit through a narrowchannel with a dressing before reaching a desired site, or target tissuesite, in vivo and delivering the dressing to the target tissue site. Thedevices described herein include mechanisms to introduce the dressinginto the GI environment from the end of a narrow channel. The devicesalso involve taking the dressing from a compact condition to a splayedcondition. In some embodiments, introduction of the dressing into the GIenvironment from the end of a narrow channel involves introducing thedressing in a compact condition. In alternative embodiments, theintroduction of the dressing into the GI environment from the end of anarrow channel involves introducing the dressing in a transitioncondition or a splayed condition as it emerges from the narrow channel.In some embodiments, the dressing is released from the device aftercontact with a target tissue site. In some embodiments, the dressing isreleased upon one or more of expansion of the expandable support into anexpanded format and adhesion of the dressing to the target tissue site.

In some embodiments, the dressing seals a target tissue site ingastrointestinal tract. In the case of the GI tract, sealing iscomplicated by the gel like nature of the mucus of the stomach lining.Attachment to this gel mucus layer is important for efficacy. In someembodiments, the adhered hemostatic dressing promotes bleeding controlpartly by sealing the wound but also by promotion of local clotformation. For example, mucoadhesive chitosan dressings are highlyeffective at stopping bleeding by sealing of the target tissue site andby providing local hemostatic promoting capability.

In one embodiment, the dressing provides a unique opportunity fortreatment of adherent clots, i.e., by reinforcing and promoting localhealing, that could otherwise fail and cause serious hemorrhage if leftuntreated. Currently there is no treatment for large adherent clotsfound in the upper GI tract other than keeping subjects under closeobservation.

In some embodiments, the dressing may further comprise a pharmaceuticalactive agent (drug or biologic) that may be delivered and appliedlocally to the target tissue site.

In some embodiments, the dressing stops bleeding at the site ingastrointestinal tract. In one embodiment, the device delivers a CGHD toa target tissue site in the gastrointestinal tract.

A long-felt difficulty and unmet need in the field of deliveryhemostatic dressings for treatment of GI bleeding relates to the abilityto introduce and apply the dressing at the bleeding site through anon-invasive or minimally-invasive way. The gastrointestinal deliverydevice of this invention meets this need by providing for a deliverydevice that can fit through a narrow channel along with a compactdressing and then providing the dressing in a splayed condition forapplication to a target tissue site. As described herein, the inventioncomprises a unique expandable support component that provides, in itsunexpanded format, for the delivery of the dressing in a compactcondition via a narrow channel. The invention also comprises a uniqueexpandable support component that provides, in its expanding format orin its expanded format, for the introduction of a splayed dressing forapplication to a target tissue dressing site.

In a preferred embodiment, once the splayed dressing is applied to atarget tissue dressing site, it is released, and the other deliverycomponents and mechanisms used to deliver the dressing are removed fromthe target tissue site. The dressing may be releasably attached to oneor both of the axis and the expandable support. The expandable supportmay be collapsed before it is removed from the target tissue site. Alldevice components other than the dressing may then be removed from thetarget tissue site.

In one preferred embodiment, the gastrointestinal delivery devicecomprises an expandable support, a wire support axis, and a releasableCGHD dressing, wherein the device is capable of fitting through achannel of 4 mm diameter or less. In some embodiments, the devicefurther comprises a protective sheath.

Definition of Terms

The following terms, including plurals and all tenses thereof, as usedin this disclosure have the following meanings.

The term “dressing” means any solid, or semi-solid, or porous,integument, or matrix structure capable of adherence to a target tissuesite. Dressings of the present invention comprise dry, compliant, planarporous articles capable of application over a planar target tissue siteor capable of compression into non-planar cavity of a target tissue siteand may interact uniformly with a surface of the target tissue site.

Dressings of the present invention include, but are not limited to,structures comprising a hydrophilic biopolymer. Preferred dressings ofthe present invention comprise chitosan or catechol modified chitosansuch as, for example, the CGHD described herein.

The term “target tissue site” means a tissue surface that is identifiedfor receipt of a dressing. The target tissue site may or may not includeopenings, holes, tears, lacerations, damaged or loose injured tissue, orother imperfections that render the tissue surface uneven or incomplete.

The term a “narrow channel” refers to any conduit measuring less than orequal to about 4 mm in diameter. The narrow channel may provide for thesafe or controlled passage of the delivery device to a target tissuesite.

The term “axis” refers to a structural support of the device. In deviceembodiments wherein the axis forms a separate component that is distinctfrom the expandable support and the dressing, it may provide for a pointof attachment for either or both of the expandable support and thedressing. The axis may form a core of the device about which theexpandable support in its unexpanded format and the dressing in itscompact condition may be configured.

The term “expandable support” refers to any structure capable of beingtransitioned from an unexpanded format into an expanding format and froman expanding format into an expanded format. In some embodimentsdescribed herein, expandable supports are also capable of beingtransitioned from an expanded format into an expanding format and froman expanding format into an unexpanded format. Transition of theexpandable support between its various formats (unexpanded, expanding,and expanded) may or may not be automatic or remotely controlled. Forexample, transition of the expandable support may occur automaticallyupon removal of a physical barrier or constraint that otherwisesuppresses the internal expansion tension of the device, such as whenthe device exits the narrow channel and/or when a sheath is ruptured. Inanother example, transition of the expandable support may be controlledremotely by triggering an expansion mechanism that causes the expandablesupport to go from an unexpanded format towards an expanded format or,alternatively, from an expanded format to an unexpanded format.Expandable supports of the present invention include, but are notlimited to, wire structures and balloon catheters. In device embodimentswherein the axis does not form a separate component from the expandablesupport, reference to the expandable support is meant to include thefunctional support features of the axis.

The term “sheath” as used herein refers to any cover, membrane, coating,or material used to enclose or envelope, either wholly or partially, oneor more of the axis, the expandable support, and the dressing.

The term “wire” refers to a generally elastic to super-elastic metalliccomponent with a high aspect ratio (generally >10) of length to widthand formed of metals including, for example, nitinol ribbon, round orelliptical gauge wire; stainless steel ribbon round or elliptical gaugewire; longitudinal laser cut nitinol or a stainless steel cylinder.

The term “splayed” means spread out, opened, unfolded, unfurled,uncrimped, or expanded. As used herein, dressings are “splayed” byapplication of mechanical force, including at the edges or out perimeterof the dressing, that cause its edges to be pulled or pushed apart;thus, splaying the dressing, or changing the configuration of thedressing from a compact condition into a transition condition and/or asplayed condition. It is noted that the dressing described herein arecapable of being “un-splayed”, i.e., compacted, closed, folded, furled,or crimped. In preferred embodiments, the dressings may be repeatedlysplayed and un-splayed.

The term “high surface area” refers to the increased dressing surfacearea of dressings capable of changing configuration from a compactcondition (minimum or near minimum surface area) into a transitioncondition (larger surface area) and/or a splayed condition (maximum ornear maximum surface area). The dressings of the present invention havea splayed configuration that provides a greater surface area relative toany dressing that may be delivered through a narrow channel that isincapable of assuming a transition condition or a splayed condition.

The term “compact condition” refers to the dressing in its closelypacked, dense, smallest configuration, which occupies the least amountof space while still being capable of passing through a narrow channel.

The term “splayed condition” refers to the dressing in its spread out,opened, unfolded, unfurled, uncrimped, or expanded. A dressing in itssplayed condition is one that has a high surface area and is ready forapplication to a target tissue site. Dressings of the present inventionmay be in their splayed condition even if they are not maximally spreadout, opened, unfolded, unfurled, uncrimped, or expanded.

The term “transition condition” refers to the dressing that is no longerin its compact condition, but not yet ready for application to a targettissue site.

The term “released” refers to a releasable dressing that is detached,unbound, untethered, or liberated from association with one or both ofthe axis and the expandable support.

The term “seals” refers to the function of a dressing to fasten orsecurely close a tissue surface at a target tissue site.

The term “removed” refers to the withdrawal of device components from atarget tissue site.

The term “unexpanded format” refers to the expandable support in itsclosely packed, dense, compact, smallest configuration, which occupiesthe least amount of space while still being capable of passing through anarrow channel.

The term “expanding format” refers to an expandable support that is nolonger in its unexpanded format and increased or enlarged in size, butthat is not yet ready to facilitate application of a dressing to atarget tissue site.

The term “expanded format” refers to an expandable support that isfurther increased or enlarged in size relative to the expandable supportin its expanding format configuration. The expandable support in itsexpanded format configuration is ready to facilitate application of adressing to a target tissue site.

The term “releasably attached” refers to the detachable connectionbetween the dressing and either or both of the axis and the expandablesupport. Releasable attachment of the present invention may beaccomplished, for example, by use of dissolvable threads, weakenedand/or perforated connection sites between the dressing and other devicecomponent(s), mechanical release or “letting go” of the dressing, etc.

The term “light pressure” refers to the amount of force applied to adressing upon contact with a target tissue site. For example, lightpressure is a pressure at about most preferably 10 kPa or less, morepreferably 25 kPa or less, or preferably 50 kPa or less (note 100g/cm²=9.8 kPa).

The term “contact” means to touch.

The term “adhere” means to hold fast or stick by or as if by gluing,suction, grasping, or fusing to the target tissue site. In oneembodiment, dressings comprising chitosan or catechol modified chitosansuch as, for example, the CGHD described herein, are held fast andunited by molecular forces acting in the area of contact with a targettissue site. After achieving intimate contact with the underlying solidand/or semi-solid tissue and/or mucosal tissue layer by displacementand/or absorption of interfering fluid, the dressing of the invention isunited to the said underlying tissue by molecular forces including vander waals (the weakest molecular force but sufficiently strong toprovide sealing to hemorrhage at 100 mmHg or 13.3 kPa), electrostaticforce between oppositely charge molecules (chitosan is generallypositively charge with this positive charge optimized at pH near pH4.5.— mucosa surface is generally decorated with sialic acid negativelycharged species), hydrogen bonding (chitosan has great facility to formhydrogen bonds), and covalent bond (Schiff base or imine functionalcovalent linkage occurs with chitosan catechol in the presence of tissuegroups including an amine, other catechol group covalent reactions canoccur with —OH and —SH functional groups at the tissue surface).

The term “rupture” when used to refer to the sheath means to break orburst suddenly, breach, split, separate, or part.

1. Axis

The axis may comprise various materials including, but not limited to,nitinol ribbon, round or elliptical gauge wire, stainless steel ribbon,round or elliptical gauge wire, or a longitudinal laser cut nitinol orstainless steel cylinder. The axis may be a wire or any other structurethat functions to deliver the expandable support and dressing and,optionally, the sheath to a target tissue site. In a preferredembodiment, the axis comprises nitinol.

Nickel titanium, also known as nitinol, (a shape memory alloy), is ametal alloy of nickel and titanium, where the two elements are presentin roughly equal atomic percentages e.g. Nitinol 55, and Nitinol 60.Nitinol 55 is the most common form of nitinol alloy. Nitinol exhibitsshape memory effect and super elasticity. In one embodiment, wire orlaser cut cylinder application of nitinol as a device component materialrelies on the super elasticity effect of nitinol. Superelasticity occursat a narrow temperature range just above its transformation temperature;in this case, no heating is necessary to cause the undeformed shape torecover, and the material exhibits enormous elasticity, some 10-30 timesthat of ordinary metal.

In some embodiments, sprung stainless steel round wire or ribbon wiremay be used for this elastic recovery device component application. Forexample, elastic recovery occurs when the sprung material is releasedfrom the sheath enclosure and the sprung material returns to itsoriginal shape releasing its potential energy as kinetic energy in theprocess. The kinetic energy is used to splay the dressing.

In some embodiments, a single structure may serve as both the axis andthe expandable support. In such embodiments where only an expandablesupport is referenced, it is to be understood that, in such embodiments,the expandable support serves as both the axis and the expandablesupport.

The axis serves as an internal support structure for thegastrointestinal device. In some embodiments, the axis comprises one ormore wires, e.g. two wires. In some embodiments, the axis comprises oneor more spring wires.

In some embodiments, the wire support axis connects to the expandablesupport either directly or by an intervening structure, e.g., anarticulated spring locator positioning arm. The proximal ends of thedelivery tube (narrow channel) and delivery wire (axis and/or expandablesupport), once the device is removed from the packaging are both alwaysoutside the proximal end of the endoscope delivery channel. The proximalend of the delivery tube is manually manipulated to position the distalend of the tube in alignment or slightly protruding from the distal endof the endoscope delivery channel. Once the delivery tube is aligned,the tube position is locked inside the endoscope delivery channel sothat it cannot progress forward or backward. Once the delivery tube is“locked” in position the proximal end of the delivery wire may be“unlocked” if locked from its positioning inside the delivery tubesheath and forward progression of the delivery wire inside the deliverytube may be accomplished by proximal delivery wire end manipulation.

2. Expandable Support

The expandable support is characterized by an unexpanded format thatfits through a narrow channel (e.g. tubing) of 4 mm diameter or less.When in an unexpanded format, the expandable support fits within adimensional space measuring about 4 mm to 2.8 mm diameter, and/oroccupies, as measured by its outermost points, a volume of about 0.38cm³ to 0.06 cm³. The expandable support is also characterized by anexpanded format. When in an expanded format, the expandable support fitswithin a dimensional cone space of 30 mm to 25 mm height and about 30 mmto 10 mm in diameter, and/or occupies, as measured by its outermostpoints, a volume of about 7.0 cm³ to 0.65 cm³.

The expandable support may comprise any structure that functions todeliver the dressing and, optionally, the sheath to a target tissuesite. The expandable support may comprise various materials including,but not limited to nitinol ribbon, round or elliptical gauge wire;stainless steel ribbon round or elliptical gauge wire; longitudinallaser cut nitinol or stainless steel cylinder, balloons formed ofelastomeric integuments such as polyurethane, polyurethane urea, latexrubber, and polybutadiene rubber. In a preferred embodiment, theexpandable support is a wire or a balloon.

In one embodiment, the expandable support comprises material formed tohave articulated spring ends.

In one embodiment, the expandable support may be repeatedly adjustedbetween an unexpanded format, expanding format, and expanded format.

The expandable support may attach to the releasably attached dressing.

In one embodiment, the expandable support, upon reaching the desiredtarget tissue site in vivo, can expand from an unexpanded format to anexpanded format. When the expandable support is in an expanding format,it may trigger the reconfiguration of the dressing to go from itscompact condition, into a transition condition, and then into a splayedcondition.

In one embodiment, the expandable support is used to apply a lightpressure (e.g. 50 to 400 g) on the dressing, allowing the dressing tocontact and adhere to the target tissue site. The expandable support mayapply a light pressure to the dressing for a period of time rangingbetween about ten (10) seconds and five (5) minutes, and more preferablybetween about twenty (20) seconds and about five (5) minutes. Forexample, a 20 second to 120 second, or two (2) minute, application timemay be suitable for low to moderate bleeding which includes a blood flowrate of about 1 ml/min to about 20 ml/min. Blood flow rates above 20ml/min may require longer hold application times of about two (2) tofive (5) minutes to provide for more secure attachment.

In one embodiment, the deployment and transition of the expandablesupport from an unexpanded format to an expanding format to an expandedformat may take about two (2) to five (5) seconds.

In one embodiment, after contacting and adhering the dressing with thetarget tissue site, the expandable support releases the dressing,thereby allowing the other (non-dressing) components of the device to beremoved and leaving the dressing at the target tissue site. In a furtheraspect, the expandable support is collapsed into its unexpanded formatbefore being removed from the target tissue site.

In one embodiment, the expandable support is an umbrella structure thatcan be collapsed and expanded as desired.

In one embodiment, the expandable support may comprise one or morewires. For example, the expandable support comprises an annular shapedwire that can be adjusted between an unexpanded format, an expandingformat, and an expanded format at a target tissue site. In someembodiments, the expandable support comprises spring wire structuresthat form, e.g., a stable balloon, in an expanding format or an expandedformat at the target tissue site. In some embodiments, the expandablesupport comprises multiple substructures, e.g., one or more of a springwire dressing support loading structure, a base support spring struts,etc.

In some embodiments, the expandable support transitions from anunexpanded format into an expanding format and/or an expanded format,and the device delivers a releasable dressing to a target tissue site.In some embodiments, the expandable support transitions from anunexpanded format into an expanding format and/or an expanded format,and the dressing transitions from a compact condition into a transitioncondition and/or a splayed condition, and the device delivers areleasable dressing to a target tissue site. In some embodiments, alldevice components except for the dressing are removed after the dressingis delivered to a target tissue site. In some embodiments, theexpandable support in one of an expanding format or an expanded formatis collapsed, or returned to an unexpanded format, before all devicecomponents except for the dressing is removed.

3. Dressing

The present invention relates to a biocompatible, foldable, thinprofile, chitosan-based dressing comprising catechol modified chitosanand characterized by one or more, or all, of the following features,such that it is: (1) able to be delivered intact by balloon or throughendoscopic device; (2) is able to wet and adhere intact to gastricmucosa in under 30 seconds with application of light pressure; (3) hascapillarity, porosity and absorbency that is able to remove hydrophilicand hydrophobic biological fluids that can interfere with adhesion; (4)is able to stay in place intact and stops moderate to oozing bleeding,e.g., a bleeding rate of between about 20 ml/min to about 100 ml/min, orgreater; (5) is able to be released from the delivery device to allowwithdrawal of the delivery device from the GI environment; (6) is ableto resist detrimental rapid breakdown (<6 hours) in the corrosiveenzymes and acidity (>pH 3) of the GI environment; (7) is able toprotect the gastrointestinal injury site for preferably up to 12 hours,more preferably up to 24 hours and most preferably up to 96 hours toassist with its subsequent acute healing and closure; and (8) is able toachieve a controlled, slow dissolution from the attachment site to allowfor unassisted complete removal in less than seven days with thedissolved residue passing safely through the alimentary tract.

Chitosan Dressing

Chitosan dressings may refer to compositions that include varyingamounts of chitosan. The general contents, general chemical compositionsand different forms of a chitosan dressing are described, for example,in U.S. Pat. Nos. 7,820,872, 7,482,503, 7,371,403, 8,313,474, 7,897,832,9,004,918, 8,920,514, 9,204,957, 8,741,335, 8,269,058, 9,205,170, and10086105. Such chitosan dressings, due to their chemical and physicalproperties as described previously, have been used to stop bleeding.

The chitosan used preferably comprises the non-mammalian material poly[.beta.-(1.fwdarw.4)-2-amino-2-deoxy-D-glucopyranose. The chitosan canbe processed in conventional ways from chitin obtained, for example,from animal crustacean shells such as shrimp. Chitosan may bebiocompatible and biodegradable within the body, and is capable of beingbroken down into glucosamine, a benign material. The catechol-modifiedchitosan used herein may include reference to catechol-added chitosan.

A chitosan dressing can be dry or wet. A chitosan dressing is “dry” ifthe moisture content in the chitosan dressing is less than about 15% byweight, preferably about 10% by weight, and more preferably about 5% byweight. A chitosan dressing is “wet” when the chitosan dressing has comein contact with a source of water, including water in a physiologicalenvironments and biological fluids, or in an aqueous solution. Forexample, a chitosan dressing becomes wet when the chitosan dressing, asdescribed in this disclosure, comes in contact with gastrointestinaltract fluid or a gastrointestinal tract tissue surface (covered bygastrointestinal mucosa). The chitosan dressing, remaining substantiallyin a solid form absorbs, displaces, redirects or channels water/moisturein the physiological environment of gastrointestinal tract in amountssufficient to permit adhesion of the chitosan dressing to the tissuesurface. The adhered chitosan dressing can be used to seal woundsurfaces and slow or stop further bleeding.

In a preferred embodiment, the chitosan gastrointestinal hemostaticdressing of the invention contains preferably greater than or equal to25% by weight chitosan; more preferably greater than or equal to 50% byweight chitosan and most preferably greater than or equal to 75% byweight chitosan. Chitosan is a generic term used to describe linearpolysaccharides that are composed of glucosamine and N-acetylglucosamine residues joined by β-(1-4) glycosidic linkages (typicallythe number of glucosamines ≥N-acetyl glucosamines) and whose compositionis soluble in dilute aqueous acid (Roberts 1991). The chitosan familyencompasses poly-β-(1-4)-N-acetyl-glucosamine andpoly-β-(1-4)-N-glucosamine with the acetyl residue fraction and itsmotif decoration (either random or block) affecting chitosan chemistry.The C-2 amino group on the glucosamine ring in chitosan allows forprotonation, and hence solubilization of chitosan in water (pKa≈6.5)(Roberts 1991). Other hydrophilic polymers such as, for example, guar,pectin, starch and polyacrylic acid may be used.

In a preferred embodiment, the dressing of the invention is polymeric,thin (preferably dry dressing thickness of about ≤500 microns, morepreferably thickness of about ≤200 microns, most preferably thickness ofabout ≤100 microns), flexible, porous, dry, biocompatible, tissueadherent and hemostatic.

The dressings are not limited in shape, however square, rectangular,circular, or circular petal shaped dressings are preferred. In oneembodiment, a maximum size could be up to about 50 mm×50 mm square or 50mm in diameter. In another embodiment, dressing size could be about 45mm×45 mm square or 45 mm in diameter, 40 mm×40 mm square or 40 mm indiameter, 35 mm×35 mm square or 35 mm in diameter, 30 mm×30 mm square or30 mm in diameter, 25 mm×25 mm square or 25 mm in diameter, 15 mm×15 mmsquare or 15 mm in diameter, 10 mm×10 mm square or 10 mm in diameter,etc. In still another embodiment, each of the length and width may rangefrom about 10 mm to about 50 mm, or from about 10 mm to about 50 mm indiameter. As dressings become larger in size they become increasinglysubject to delivery limitations in confined cavities such as thestomach, etc.

Dressings described herein may provide a large dressing surface area inan open, unfurled, or unfolded condition. Alternatively, dressingsdescribed herein may provide a small dressing surface are in a closed,furled, or folded condition. The ability of the dressings to be folded,furled, or closed allows them to be more compact and protected fordelivery and reduces the likelihood that the dressing surface isprematurely wetted prior to delivery to a target tissue treatment site.

In a preferred embodiment, the dressing is about 50 microns thick, isabout 2.5 cm in diameter, and will have an open, unfurled, or unfoldedoutward facing surface area of about 9.856 cm². Inside the deliverydevice sheath (wall thickness of a typical fluorinated ethylenepropylene (FEP) delivery tube is about 150 microns), a closed, furled,or folded dressing will have an outward-facing cylindrical surface area(in a 1.25 cm long cylinder) of about 2.07 cm² inside a 0.45 cm diametergastroscope channel, or about 1.56 cm² inside a 0.32 cm diametergastroscope channel; or about 1.41 cm² inside a 0.28 cm diametergastroscope channel. Thus, in one example, a dressing of the presentinvention may, in an open, unfurled, or unfolded condition, have anoutward facing surface area that is about six (6) times greater, aboutfive (5) times greater, or about four (4) times greater than the outwardfacing surface area of that same dressing when it is in a closed,furled, or folded condition. In some embodiments, the ratio of theoutward facing surface area of an open, unfurled, or unfolded to aclosed, furled, or folded dressing is about 15:1, or about 14:1, orabout 13:1, or about 12:1, or about 11:1, or about 10:1, or about 9:1,or about 8:1, or about 7:1, or about 6:1, or about 5:1, or about 4:1, orabout 3:1, or about 2:1.

It is noted that the most common gastroscope channel is 0.28 cm diameter(2.8 mm) and hence this is the most preferred size for the dressingdelivery. Alternatively, a more preferred size is 0.32 cm diameter,which is a standard gastroscope channel diameter but less common thanthe 0.28 cm channel. Another preferred gastroscope channel diameter sizeis between 0.45 cm and 0.32 cm which is more a custom gastroscopechannel size and, thus, less common than the 0.32 or the 0.28 cmgastroscope channel diameter size.

It is able to be folded and unfolded, is not readily soluble in blood orbody fluid at about 37° C. within, preferably, the first 6 hours ofapplication, more preferably the first 12 hours of application, and mostpreferably the first 24 hours of application, and degrades and/ordissolves fully in contact with gastrointestinal fluids at about 37° C.within about 7 days.

It will not adhere to the delivery device, and does not swell or shrinkappreciably, i.e., it does not increase or decrease in size by more thanabout 25% in length and width, or more than about 50% in thickness, inthe presence of blood and GI fluid at about 37° C.

In a preferred embodiment, the dressing may be terminally sterilizedwithout affecting dressing characteristics. When it is stored undercontrolled conditions in its packaging at room temperature of about 21°C. to about 25° C., its tissue adhesion properties, mechanicalproperties, dissolution properties in gastrointestinal fluid, swellingproperties, and hemostatic properties are stable and do not changeappreciably over time (e.g., about ≤2 years).

A preferred embodiment, the dressing has a tissue adhesive side and anon-adhesive side. In this embodiment, the non-adhesive side may providea surface that when wet readily slides away from itself and from anyapplicator or delivery device surface that is applying pressure againstthe dressing inside a lumen, and/or in the gastrointestinal tract.

A preferred embodiment of the dressing is that it is formed of asubstantially dry chitosan composition with a water content of about≤15%, or about ≤8%. The dry chitosan composition is preferably formedusing phase separation and drying of an aqueous solution of chitosan andwater. The dry chitosan dressing is preferably prepared in sheet formwhich may be cut to size.

Preferred embodiments of the biocompatible, bio-dissolvable, tissueadherent chitosan dressing are able to resist dissolution ingastrointestinal (GI) fluid and blood at about 37° C. for at least about6 hours is tissue adherent and includes materials and materialstructures that promote resistance to rapid dissolution and degradationin the low pH and strongly enzymatic digestive fluid of the uppergastrointestinal tract. This is a significant advantage of the chitosandressings disclosed herein because the upper gastrointestinal digestivetract has evolved to rapidly digest most organic materials includingchitosan, cellulose and starch.

Chitosan dressings provided herein can be applied to a mucus surface,e.g., in gastrointestinal tract by light pressure. Light pressureapplied to the dressing on a tissue surface as used herein indicates apressure that attaches and keeps a chitosan dressing in contact with aninjury site without significant deflection or movement of the tissue soas to allow the chitosan dressing, through its compositional structuresand characteristics, to interact to promote adherence with the injurysite to stop bleeding. In some embodiments, a light pressure is apressure at about most preferably 10 kPa or less, more preferably 25 kPaor less, or preferably 50 kPa or less (note 100 g/cm^(2=9.8) kPa).Typically there is significant deflection on application of load above100 kPa to soft tissue such as the stomach making application ofpressure without a supportive opposite pressure impossible. Anexploration of the elastic modulus of the human stomach is provided inSaraf et al. 2007. Saraf, H. et al., Mechanical properties of soft humantissues under dynamic loading, J. OF BIOMECHANICS, 40(9), pp. 1960-1967(2007).

Production of Chitosan Dressing

The chitosan dressings of the present invention may be generated usingvarious methods and processes. In some embodiments, the chitosandressing may be formed by freeze phase separation and drying. In analternate embodiment, the dressing is formed by addition of a foamingagent to provide a low density foam before freezing followed by drying.Freeze phase separation followed by removal of frozen solvent bysublimation is called freeze drying. Freeze phase separation is aprocess of solidification from dilute solution whereby removal of heatand resultant lowering of temperature through a container or moldsurface holding the dilute solution results in a localized solid crystalnucleation of pure solvent and subsequent propagation and growth of puresolvent crystal. A result of the pure solvent crystal growth in a dilutesolution is that solute diffuses away from the growing crystal front tosolidify at the interstices between the growing crystal. Freeze phaseseparation of dilute polymer aqueous solutions results in alternatelayers of thin polymer lamella between thicker layers of ice. Removal ofthe ice by methods which do not disrupt the polymer lamella results in alow-density polymer dressing with inter-connected porous structure. Forexample, in one embodiment, low-density polymer dressings may have aninitial dressing density from about 0.005 g/cm³ to about 0.05 g/cm^(3.)

In an alternate embodiment, the freeze phase separated dressing isformed by freezing of a foamed dilute solution followed by drying. In analternate embodiment, the dressing is formed by non-woven fiber spinningprocesses, such as centrifugal spinning, electrospinning or solventfiber extrusion into a coagulation bath. In yet another alternateembodiment, the dry dressing of the invention may be formed from a wovenfiber process. In yet another alternate embodiment, the dry dressing ofthe invention may be formed by phase inversion and precipitation with anon-solvent (as is typically used to produce dialysis and filtermembranes). In still another alternate embodiment, the dressing of theinvention may be formed from an additive 3D printing process.

In a preferred embodiment of the invention, the dressing preparationprocess may include a compression process that changes the initialdressing density from an initial preferred range of about 0.005 g/cm³ toabout 0.05 g/cm³ to a final preferred range of about 0.03 g/cm³ to about0.7 g/cm³; however, ranges of about 0.08 g/cm³ to about 1.2 g/cm³ arealso contemplated. It is noted that a density of about 1.5 g/cm³ is thedensity of void-free chitosan dressings. The compression process mayinclude application of temperature in the range of about 20° C. to about150° C. To avoid substantial dressing swelling of the dry compresseddressing on contact with biological fluid, the temperature of thecompression is preferably applied by a method that may include but notbe limited to convection, conduction and radiation, and the temperatureof the compressed dressing should preferably be maintained at leastabout 80° C. for at least about 15 seconds.

Heat during compression is a tool that allows plasticization and moldingof the chitosan without cracking or tearing of the chitosan(non-destructive molding). The first glass transition temperature (Tg)of pure dry chitosan is near 80° C. which if processed near in the caseof pure dry chitosan will allow ready non-destructive molding of thechitosan as well as some crystalline annealing of its structure. It ispossible to lower the Tg by application of plasticizers such as water orglycerol to the chitosan and hence provide a similar level ofnon-destructive molding at lower temperature. Here, it is noted thatchitosan can be molded non-destructively in the range 20° C. to 150° C.Outside of this range it would still be possible to non-destructivelymold the chitosan but much more difficult. Above 150° C. the chitosanbegins to thermally degrade while below 20° C., the addition ofplasticizers may lead to undesirable loss of chitosan crystallinitywhich provides for dissolution resistance and resistance to degradativeprocesses such as occur in sterilization.

Preferably, the compression prevents substantial swelling of the drycompressed dressing on contact with biological fluid and is performedwith moisture content of the dry dressing during the compression atabout ≤15% w/w. The compression may be applied through twin ormulti-roller compression and/or uniaxially between adjacent platens.

The compression may be against a uniform flat or curved surface toprovide a smooth finish to the compressed dressing.

Alternatively, the compression may be applied against an etched,machined, ablated or other type of surface treatment that imparts adepleted or added surface texture. The surface texture may be a randomor it may be a regular repeated pattern. The pattern of the surface mayassist in folding and unfolding or furling and unfurling the dressingand may provide for hinge-like properties in the dressing. Such texturemay be used as an adjunct to quickly lock the dressing in place and stopit moving when applied. Movement of the surface of the dressing whilepositioned against the target tissue surface can cause filming and henceclosure of the open surface structure which can lead to loss ability toremove anti-adhesive biological fluid at the surface and hence loss ofability to adhere the dressing to the surface. The timescale of thechanges occurring at the dressing surface is very important such thatsurface uptake of fluid with significant surface dressing channelclosure is highly undesirable. A good way to avoid such movement is tophysically fix the dressing in place as soon as it contacts the tissuesurface.

Prior to the present invention, thin solid chitosan dressings weregenerally rigid, not flexible enough to be bent or folded or furledwithout breaking, fracturing, or otherwise losing their intact shape orbecoming otherwise unsuitable for use. Chitosan dressings providedherein, due to their compositional structures and characteristics, canbe folded and unfolded along a folding axis while still being intact andsuitable for use in stopping bleeding. Interestingly, and contrary toexpectation, it has been found that chitosan dressings described herein,when folded, become less resistant to tearing or breakage along theirfolded seams. In some embodiments, the chitosan dressing providedherein, due to its compositional structures and characteristics, can befurled without losing its compositional structures and characteristicsand still being intact and able to stop bleeding. In some embodiments,the chitosan dressing provided herein, therefore, is able to bedelivered through a narrow working channel while still maintaining theircompositional structures and characteristics intact. Exemplary diametersof a narrow working channel through which the chitosan dressing providedherein can be delivered include a diameter of about 3.2 mm or less, andincluding, but not limited to, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm,0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1.0 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm,1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm,2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, and 3.2mm.

Catechol Modified Chitosan; and Its Production

The chitosan dressings described herein relate to chitosan dressingscomprising catechol modified chitosan and/or hydrophilic polymers. Otheraspects of chitosan dressing comprising catechol modified chitosan aredescribed in more details below.

Preferred embodiments of the chitosan gastrointestinal dressing of theinvention include compositions with catechol modified chitosan and/or,optionally, other hydrophilic polymers. Preferably the catechol modifiedchitosan in the dressing provides prolonged adherence to wetted tissuewith tissue adherence ≥about 1 kPa resisting dissolution in water,saline solution, blood and/or GI fluid at about 37° C. for ≥about 6hours. Preferably the catechol modified chitosan is formed byN-acylation of the C-2 amine on the chitosan glucosamine by3,4-dihydroxyhydrocinnamic acid (alternatively named3-(3,4-Dihydroxyphenyl)propionic acid, Hydrocaffeic acid)).Alternatively, the chitosan N-acylation to produce a catechol modifiedchitosan may include but not be limited to a modification with one of a3,4-Dihydroxycinnamic acid (caffeic acid); a trans-3,4-Dihydroxycinnamicacid (trans-caffeic acid); and a 3,4-Dihydroxyphenylacetic acid (DOPAC,Homoprotocatechuic acid).

The presence of catechol in the composition provides for somepoly-conjugated structure as the catechol is oxidized to o-quinone. Thiscauses visible difference between the unmodified chitosan and catecholmodified chitosan compositions, which may be off-white or pink to darkbrown in color, respectively. It is noted that the catechol modifiedchitosan compositions go from pink to brown when oxidation occurs in thecatechol.

Pink coloration in the catechol modified chitosan, signifyingsubstantial absence of crosslinking, is provided in the aqueoussynthesis by maintaining pH reaction solution at or below pH 5.5. Thepink coloration may also be provided in the aqueous synthesis byperforming the modification and subsequent processing stepssubstantially in the absence of oxygen such as by using aqueous systemspurged with an inert gas which may include but not be limited to argonor nitrogen. Although the pink coloration is not desirable in the finalsolution or catechol modified product, it may be desirable inintermediate handling stages (such as immediately after chitosanderivatization with catechol and/or dialysis and/or washing of thesubsequent catechol chitosan solution to remove residual unreactedmaterial) because it allows for stable dry product polymer storage anddry product weight determination with subsequent ability tosubstantially re-dissolve the pure dry catechol modified product inwater to a desired dry weight at a later time. This water-solublechitosan catechol material is then subsequently oxidized and crosslinked(with brown coloration). However catechol modified chitosan which isdried before oxidation is not suitable for use in the chitosan dressingof the invention because dressings including such treated catecholmodified chitosan are not readily redissolved and the final solutionincludes an undesirable mass fraction (>5% w/w) of insoluble particulate(>10 microns in diameter). Additionally catechol chitosan prepared afteran intermediate freeze drying stage is more prone to early dissolutionin gastrointestinal fluid.

In a preferred embodiment, the catechol modified chitosan is not removedfrom solution by an intermediate drying step to allow for storage butrather it is kept in aqueous solution and oxidized in aqueous solutionby exposure to higher than about pH 5.5 in the presence of atmosphericoxygen. Preferred pH control is achieved by adjustment of partialpressure of aqueous dissolved carbon dioxide (increased partial pressurereduces pH while decreased partial pressure increases pH to nearer pH7). An alternative preferred means of pH control is by incrementaladdition of a strong acid to lower pH and a strong base to raise pH.Examples of strong acids may include, but are not limited to,hydrochloric acid, sulphuric acid and nitric acid. Examples of strongbases may include but not be limited to sodium hydroxide and potassiumhydroxide. Subsequent drying of this aqueous water-soluble oxidizedcatechol modified chitosan results in a preferred level of crosslinkingof the catechol chitosan with good resistance to dissolution anddegradation in the upper gastrointestinal tract. The catechol chitosansolution may be diluted by addition of water or concentrated by waterremoval. The water may be removed by the techniques including, but notlimited to, ultrafiltration, reverse dialysis and centrifugation. Thesolid fraction of the solution may be determined by sampling a knownvolume from the solution and performing analyses including but notlimited to gravimetry, Fourier transform infrared spectroscopy,ultraviolet-visible spectroscopy, refractometry, and pycnometry.

In a preferred embodiment, the catechol modified chitosan composition isof a brown color resulting from catechol oxidation to o-quinone. Thequinone is produced by autoxidation of the catechol hydroxyls in thepresence of oxygen and at pH above about 5.5. Schiff base reaction ofquinone with chitosan C-2 amine produces crosslinking in the modifiedchitosan. The color of the catechol modified chitosan composition iscontrolled during synthesis by controlling pH and oxygen exposure.Maintenance of pH at or below about pH 5.5 inhibits the production ofo-quinones. Subsequent conditioning of dialysis solution, final washed,or dialysed catechol chitosan solutions in a preferred pH range 5.8 to6.2 provides for more dissolution resistant, darker, more oxidizedcatechol. In some embodiments, the coloration of catechol modifiedchitosan characterizes one aspect of the catechol modified chitosandressing. In some embodiments, the coloration reflects the degree ofsubstitution of the chitosan with catechol. In some embodiments, thecoloration from pink to brown correlates with the degree ofsubstitution. FIG. 5 shows exemplary embodiments of differentcolorations reflecting and correlating with different degree ofsubstitution of the chitosan with catechol.

In order to prepare a dry dressing from the catechol chitosan, apreferred light brown to darker brown catechol aqueous chitosan solutionis prepared which may be used by itself or may be mixed with otheraqueous hydrophilic polymer solutions including but not limited tosolutions of chitosan and/or, optionally, hydrophilic polymers.Preferably, the dry phase separated catechol chitosan dressings areprepared as densified dried freeze-phase-separated and fibrous dressingstructures.

Preferred crosslinked catechol modified chitosan compositions of theinvention provide good tissue adherence and 10 times to 100 timesincreased resistance to dissolution in the upper gastrointestinal tractcompared to dressings formed substantially of unmodified chitosan. Forexample, FIGS. 6A-6C show dissolution testing results demonstrating thatchitosan dressings are gone in 15 minutes while some catechol dressingslasted greater than 24 hours. The catechol modified chitosancompositions described herein, provide hitherto unknown longevity,biocompatibility, and ability to eventually dissolve.

Preferred rapid adherence to gastrointestinal mucosa of the chitosangastrointestinal dressings of the invention (≤1 minute) is provided inthe dry chitosan dressing by the promotion of quaternary ammonium cationformation at the chitosan glucosamine C-2 amine by the presence of anacid in the dry dressing composition. Preferred chitosan acid salts inthe dressing may include salts of acetic, lactic, glycolic, citric,succinic, malic, hydrochloric, glutamic, ascorbic, malonic, glutaric,adipic, pimelic, and tartaric acids, and combinations thereof.Preferably the acid salt % weight of the chitosan is greater than about2% and less than about 15%. To achieve fast adherence (e.g., ≤1 minute)to wet tissue, the moisture in the dry gastrointestinal dressing ispreferably less than about 15% by weight; more preferably it is lessthan about 10% by weight and most preferably it is less than about 5% byweight.

In the case of densified freeze-phase-separated and dried chitosandressings, the chitosan solution is poured into thefreeze-phase-separation mold (typically in the shape of a pan with ahorizontal flat base) with preferably around a 0.1% w/w, more preferablyaround 0.5% w/w and most preferably 0.25% w/w hydrophilic polymerchitosan solution. The hydrophilic polymer solution is preferably addedto the horizontal flat pan to a vertical depth of preferably about 10mm, more preferably 2.5 mm and most preferably 5.0 mm mold depth. Thesolution in the mold is subsequently frozen and dried to remove water bysublimation or freeze phase substitution (solvent extraction of the icewith a non-solvent to the polymer) to a low density (>99% void volume)open or porous dry sponge with a dry density <about 0.01 g/cm³ (or, forexample, about 0.005 g/cm³ for a catechol chitosan uncompressed dressingfrom 0.5% solution, which is about ⅕ or 20% of the density of anuncompressed HemCon Bandage chitosan sponge, which is about 0.025g/cm³). Lyophilization is typically performed at pressure below 300mTorr while freeze substitution involving a dry, cold (e.g., <−20° C.)solvent such as ethanol is performed at atmospheric pressure. The drysponges are then compressed, preferably to greater than about 0.4 g/cm³density and less than about 100 microns thickness. The preferredcompression is not limited to but may include uni-axial compressionbetween aligned flat platens, wherein the platens are heated between 18°C. and 150° C. and are pressure loading up to 10,000 bar.

The preferred compression creates a remarkably thin (e.g., range fromabout ≤50 microns to about ≤200 microns) strong (e.g., 5 MPa to 25 MPaUTS) readily foldable chitosan dressing that may be placed minimallyinvasively anywhere in the body in a confined folded form that can bereformed without compromised performance to the original unfoldeddressing form for accurate and effective high surface area placement andattachment.

Foldability is addressed in the examples below. In one embodiment, foldtesting involved folding the horizontally planar final compressedcircular dressing through 180° edge over edge, first in an anticlockwisedirection, holding the edges together and compressing firmly in themiddle of the dressing to create a single linear fold axis (or crease)in the dressing. The folded dressing is then opened and the edge to edgefold is reproduced in the new fold axis but with the folding in theopposite clockwise direction. Foldability success can be rated as notears or cracks being visible along the fold axis and no significantloss in tensile properties of the dressing (determined by gentle pullingacross the fold of the dressing). FIG. 7 shows a catechol modifiedchitosan dressing that has been folded and unfolded, remaining intact,with visible fold axis (crease).

Freeze phase separation of dilute aqueous polymeric solutions results inphase separation of micron and submicron thin polymeric chitosan lamellainterspersed regularly between ice crystal sheets close to 200 micronsin width. Removal of the ice by sublimation (freeze drying) oralternatively by solvent extraction leaves the dry sponge composed ofclose-to-aligned, thin (≤1 micron), polymeric chitosan lamella.Compression of the polymeric chitosan lamella at close to or greaterthan their glass transition temperature (Tg for dry chitosan is near 80°C.) allows for their compression into the thin (near 50 microns) densepolymeric structure formed of layers of hundreds of strong compliantpolymeric chitosan leaves (lamella) which do not readily propagatecracks and which can be folded repeatably without failure. Suchmulti-leaf layering achieves remarkable strength. Prior to the presentinvention, no one has previously investigated high-densityfreeze-phase-separated chitosan dressings for manufacture and use asdescribed herein and with the aim to address key problems solved by thepresent invention such as, for example, adhesion by removal ofinterfering fluids (by absorption, channeling, displacement, and/orre-direction), ability to form a fold axis and ability to resistmechanical failure on repeated folding and unfolding along the foldaxis.

In one embodiment, porosity (void space>99%) is complete anduninterrupted in the non-compressed dressing with pore size range of20-300 microns with substantially most of the pores near 100-200microns. The un-interrupted pore structure is indicated in thecompressed dressings by their ability to absorb biological fluid such asblood.

In some embodiments, crack free, clean edge holes near 500 microns indiameter may be formed in the dressing after compression by localizedapplication of narrow gauge (near 500 microns in diameter), sharppointed needle through the dressing and into a flat, hard elastomericsurface applied immediately against the dressing which may receive andrelease the point of the needle. Preferred receiving support flatsurfaces include but are not limited to clean, dry thermoplasticelastomers with Shore 55D to 90D in hardness. Alternative methods ofhole formation may include but not be limited to use of a small diameter(near 500 microns) hole punch or a laser cut hole.

In some embodiments, chitosan dressing provided herein has holes in thedressing. In some embodiments, the holes receive fiber or otherreinforcing attachment elements. Such reinforcing element may be formedby simple local application of a reinforcing fluid to locally bind withthe edges of the holes. A reinforcing fluid used in the development ofthe present invention included cyanoacrylate glue which bound thecompressed chitosan lamella of the dressing together and prevented localdelamination and fibrillation of the chitosan at the hole stress point.Another embodiment of a hole reinforcing element is micro-moldedinterlocking parts of plastic or metal (preferably dissolvable and/ordegradable in the upper gastrointestinal tract or alternate area in thebody of application) that are placed on one side of the hole and theopposite hole side to permanently fit together and be able to supportload through the hole without causing dressing delamination,fibrillation or other stress related failure at the dressing hole whenloaded. In some embodiments, the micro molded parts may include the parton the side of the attachment to a delivery device that enablesconvenient snap-on attachment and snap-off detachment of the dressing tothe delivery device.

As used herein, the term fold axis is intended as part of the dressingsheet which demonstrates memory in the material of bending stress and orfolding and is typically localized to narrow regions of high bendingstress and shear. A crease in folded paper is an example of a fold axis.

In a preferred embodiment, the tissue adhesive component of the dressingis formed from a freeze phase separated and dried chitosan sheet withcomposition including a catechol chitosan. In a preferred embodiment thenon-tissue adhesive component of the dressing is formed from a freezephase separated chitosan dried sheet without any modified chitosan. In apreferred embodiment, both tissue adhesive and non-tissue adhesive drysheets have density ≤about 0.03 g/cm³ before compression to finaldensity ≥about 0.4 g/cm³.

In order to prepare one dressing from both sheets with the dressinghaving a tissue adhesive surface layer and a non-adhesive surface layer,the two sheets are bonded together by, for example, placing one sheet ontop of the other and applying sufficient uniform pressure over thedressings to compress them to a higher density. In a preferred process,the original densities of each sheet type at ≤about 0.03 g/cm³ isincreased to a final dressing density ≥about 0.30 g/cm³. In a morepreferred process, the original densities of each sheet type at ≤about0.015 g/cm³ is increased to a final dressing density ≥about 0.4 g/cm³.In a most preferred process, the original densities of each sheet typeat ≤about 0.01 g/cm³ is increased to a final dressing density ≥about 0.5g/cm³. At the conclusion of the compression, the two compressed sheetsare bonded together so that one cannot be readily peeled away from theother and the dressing can be manipulated by folding and furling withoutany occurrence of separation.

This physical adherence of materials by compression of two or more lowdensity porous materials together to form a final two or more layerporous material of higher density solves a difficult problem of how toadhere such materials together without physical or chemical change tothe individual materials and without addition of further bonding agentsor adherents. It is contemplated that bonding may be attributed tomicrosurface impingement and penetration of the dressings through theirpores with physical interlocking due to pore compression. This physicalinterlocking of low density, freeze phase separated, dry sheets is notrestricted to two materials of the same thickness or to only two layerssince the interlocking effect is neither sidedness nor thicknessdependent. Therefore a multi-layered construct of individual freezephase separated and dried sheets of the same or different materials ofthe same or different thickness may be formed by layering the lowdensity sheets (preferably with density ≤0.05 g/cm³) and compressing theassembly together to a density ≥0.3 g/cm³). Such a final physicallyadhered assembly would be expected to provide advantages of thin top andbottom surface layers including but not limited to adhering oranti-adhering materials with layers inside providing including but notlimited to structural, physical and chemical elements.

In some embodiments, a chitosan dressing has an adhesive side and anon-adhesive side. In some embodiments, the adhesive side of thechitosan adheres to a tissue and absorbs and/or redirects the surfacemoisture. In some embodiments, the non-adhesive side detaches from adelivery device upon attachment of the chitosan dressing to the injurysite wherein the chitosan dressing has become wet. This is in partbecause the adhesion strength of the chitosan dressing to the tissuesurface controls the dressing location upon detachment of the dressingfrom the delivery device. Detach or “readily detach” as used herein in atwo-sided chitosan dressing indicates that the chitosan dressing, withits adherent side applied to a tissue surface or an injury site andadhered due to absorbance of moisture, stays at the tissue surface orinjury site while the non-adherent side releases from the deliverydevice, thereby allowing the delivery device to be retracted from theinjury site without disrupting the position of the chitosan dressing onthe tissue surface or injury site. In some embodiments, the chitosandressing, when dry, attaches to the delivery device, thereby allowingdelivery of the chitosan dressing along with the device onto an injurysite.

In one embodiment, there is a need to attach the dressing locally to thedelivery device. Generally, these local attachment areas are at theextremity of the dressing. For example, one design is to provide forlocal pinpoint attachment on the dressing extremity tabs at thecircumference of the dressing and for no other attachment locations toavoid the risk of attaching the dressing to the delivery sheath, thedelivery device, or itself (when furled/folded). The attachmentlocations may be designed to weaken when wet or alternatively beactivated for release by some type of physical release mechanism.

In one mechanism, chitosan dressing provided in this disclosure is ableto stop bleeding by absorbing, channeling, and/or redirecting thehydrophilic and hydrophobic fluids at an injury site. The absorptionclears enough moisture from the injury site to allow subsequenthemostatic reactions between the chitosan dressing and the tissue at theinjury site, which in turn stops bleeding and allows the chitosandressing to stay attached; thus, sealing the injury site. The porous,dense, and multi-layer structure of chitosan dressing provided hereinfacilitates the absorption, channeling, and/or redirection of themoisture at the injury site, and the attachment or adherence of thechitosan dressing to the injury site.

The chitosan dressing disclosed herein is biocompatible. In someembodiments, the dissolved residue from a chitosan dressing applied toan injury site in vivo passes safely through the alimentary tract and isexcreted along with other bodily waste.

More than one, or multiple, chitosan dressings may be used or applied inserial fashion to a tissue treatment site or injury site. When more thanone chitosan dressing is deployed, such dressings may separately adhereto adjacent tissue site or injury site areas, or may overlap with eachother to varying extents. Due to the thinness of the chitosan dressingdescribed herein, depending on the application, it is contemplated thatmultiple chitosan dressings may be used as needed to promote or achievehemostasis of an injury site.

In one embodiment, the chitosan dressings overlap one another uponapplication. In such an instance, ideally there would be some adherenceof the wetted adhesive side of the subsequent dressing to the wetteddressing backing of the earlier dressing. Accordingly, in oneembodiment, the chitosan dressing does not have an anti-adherent backingbut does have a backing with a weak wet adherence that provides forsufficient adherence for placement of a subsequent overlapping chitosandressing.

Freeze phase separated dressings are composed of compacted layers offriable and delamination prone lamella that require special attachmentof the dressing to wire and cylindrical laser-cut delivery devices. Eachdressing attachment point to the delivery device must be able towithstand at least 50 to 100 g of load (use of units of mass, such asgrams, in this and in similar contexts herein, means a loadcorresponding to the weight of the recited mass) during furling andunfurling of the dressing. Because of the low cohesion strength ofsurface lamella, direct adhesion (such as by cyanoacrylate glue) of thedressing to the delivery device is not an option for freeze phaseseparated dressings formed from well dissolved solutions. One embodimentwhere this is less problematic is where the catechol chitosan is formedfrom carbonic acid dissolved chitosan wherein the base precipitated andsubsequently water-washed pure chitosan aqueous gel before dissolutionin the carbonic chitosan contains a dispersion of solid chitosan fibers(≥0.2% w/w of the chitosan) insoluble in the carbonic acid that providereinforcement to the subsequently catechol modified chitosan fromcarbonic solution. Besides this carbonic acid chitosan instance of a lowfraction (0.2% to 5% w/w of the chitosan) chitosan fiber reinforcementof the freeze phase separated bulk and surface structure of thedressing, the preferred manner of local reinforcement and attachment ofthe dressing to the delivery device in the case of wire delivery is byplacement of small diameter (near 500 microns), through and throughholes with reinforcement elements in the dressing at the points ofattachment to the delivery device.

Preformed holes in the freeze phase separated, dried dressing sponge area preferred way to make receiving holes in the uncompressed dressingsponge. Because the low density uncompressed sponges (<0.05 g/cm³)readily delaminate, are highly friable and thus cannot receive normalhole making approaches which involve any load on the sponge, thepreferred method to make holes in these sponges without any damage tothe sponge lamella structure is to apply insulating, hydrophobic(non-adherent) rod mandrels to the mold solution (from the top of thesolution, through the solution to the other side and contacting the basesurface of the mold and preferably through the base surface and into thebase of the mold) immediately before freeze phase separation of thesolution. These mandrels may be tapered to allow ease of removal afterdrying of the freeze phase separated sponge. It is envisioned that suchmandrels would be made of a rigid or semi-rigid hydrophobic materialthat could be machined or molded. Mandrel materials that would besuitable include but are not limited to the fluorinated materialsTeflon™ and Kel-F™ and high density polyethylene (HDPE). The diameter ofthe hole made after removal of the mandrel is designed to allow threadto be easily placed through friable uncompressed sponge without damageto the sponge. The mandrels may be supported in the mold by slottinginto suitably sized receiving holes in the mold base surface.Alternately they may be supported by a sheet of releasable hydrophobicfilm placed immediately over the upper surface of freeze phaseseparation mold and the mold solution. This film would be removed fromthe frozen phase separated surface, leaving the mandrels in place,before drying in the case of drying of the freeze phase separatedsolution. After drying, the preformed holes are thus ready to receivetie thread for attachment of dressing to delivery/deployment device. Thetie thread is positioned in sponge before compression in suitablearrangement to take all the forces on dressing furling, unfurling, anddelivery. Compression of sponge (from low density <0.05 g/cm3) to highdensity (>0.4 g/cm3) locks the tie thread and any other element ofreinforcement/attachment in place. The thread may be glued in placebefore or after dressing compression or the thread may be used tolocally apply a liquid reinforcing element such as cynanoacrylate gluelocally through the hole with the thread removed after application. Analternate embodiment for forming suitable holes in the uncompressedsponge for taking a supporting thread or other type of supportingelement is by laser hole cutting.

Crack free, clean edge holes near 500 microns in diameter may be formedin the dressing after compression by localized application of narrowgauge (near 500 microns in diameter), sharp pointed needle through thedressing and into a flat, hard elastomeric surface applied immediatelyagainst the dressing which may receive and release the point of theneedle. Preferred receiving support flat surfaces include but are notlimited to clean, dry thermoplastic elastomers with Shore 55D to 90D inhardness. Alternative methods of hole formation may include but not belimited to use of a small diameter (near 500 microns) hole punch or alaser cut hole.

Holes in the dressing can receive fiber or other reinforcing attachmentelements. Such reinforcing element may be formed by simple localapplication of a reinforcing fluid to locally bind with the edges of theholes. A reinforcing fluid used in the development of the presentinvention included cyanoacrylate glue which bound the compressedchitosan lamella of the dressing together and prevented localdelamination and fibrillation of the chitosan at the hole stress point.Another embodiment of a hole reinforcing element is micro-moldedinterlocking parts of plastic or metal (dissolvable in the uppergastrointestinal tract or alternate area in the body of application)that are placed on one side of the hole and the opposite hole side topermanently fit together and be able to support load through the holewithout causing dressing delamination, fibrillation or other stressrelated failure at the dressing hole when loaded. It is envisioned thatsuch micro molded parts may include the part on the side of theattachment to the delivery device that enables convenient snap-onattachment and snap-off detachment of the dressing to the deliverydevice.

General delivery device release of dressing may be achieved by a numberof methods include snap-off detachment. A preferred method of dressingrelease is by using a delivery device to dressing attachment fiber thatis strong when dry and weak when wet. Such fiber includes but is notlimited to chitosan fiber that has been treated to become rapidly watersoluble. Preferred chitosan fiber is water soluble multifilament fiberwith strength >30 MPa when dry and <than 0.1 MPa when wet.

The chitosan dressing provided in this disclosure may be used to stopbleeding in suitable diseases, conditions, disorders, or emergenttraumas or injuries. In some embodiments, the dressing may be used tostop bleeding from any wet physiological surface, e.g. mucus. Exemplaryapplications include, but are not limited to, gastrointestinal tractbleeding, other intraluminal applications, including vascularapplications, internal surgical bleeding, internal biopsy bleeding,internal bleeding following parenchymal organ resection, and oral,ocular, auditory or nasal bleeding. Additional applications that mightrequire addition of water or fluid to encourage adhesion of the chitosandressing to a tissue surface or injury site are also contemplated, forexample, use of the chitosan dressing on external body surfaces.

Chitosan dressings of the present invention may be used for treatment ofgastrointestinal bleeding that may include but not be limited totreatment of bleeding in esophageal varices, bleeding from pepticulcers, bleeding from duodenal ulcers, bleeding associated with biopsyof the upper and lower gastrointestinal tracts, resections of the upperand lower gastrointestinal tracts, and tears or ruptures in the upperand lower gastrointestinal tracts. Other diseases, conditions,disorders, or emergent traumas or injuries may include, but are notlimited to, internal arterial injury; internal bleeding from the liver,internal bleeding from the vena cava; injury in the thoracic cavityincluding perforations of the heart and lungs and their vessels; andinjuries of the abdominal cavity.

4. Sheath

The sheath is a preferred component of the device. Protectivecharacteristics of the sheath may include, provision of a slidableovercoat to better ensure easy or unobstructed movement of the axis,expandable support, and dressing through and out of a narrow channel,protection of the dressing from premature wetting in the in vivoenvironment, protection of the device from any contamination that may beintroduced upon loading into a narrow channel for delivery, andprotection of the subject to treated with the device by limitingexposure to the expandable support and dressing until such componentreach a target tissue delivery site.

Because an endoscope delivery channel is also a channel for flushing andirrigating, it may be continuously wet. In some embodiments, thedressing of the present invention cannot be allowed to become wet beforeits delivery to the target tissue site; thus, a protective sheath may bean essential component of the device. The wire is manufactured to fitinside the delivery tube (or sheath). In preferred embodiments, thesheath is a protective sheath that partially or wholly envelopes (orencloses) the expandable support and dressing. In some embodiments, thesheath overlies or envelopes the entirety or a portion of the expandablesupport and/or dressing. For example, the sheath may partially or whollyenvelop the expandable support and dressing when the expandable supportis in an unexpanded format and the dressing is in a compact condition.In some embodiments, the sheath partially or wholly envelopes the axisalong with the expandable support and dressing. The distal end of thedelivery sheath is preferably sealed from ingress of external moistureby an easily rupturable end. Preferably this rupturable end is formed ofa rupturable diaphragm inside the end of the delivery sheath thatprotects the dressing inside the sheath from premature contact withmoisture. The delicate diaphragm is protected inside the distal end ofthe delivery sheath so that handling or delivery sheath passage down theinside of the endoscope delivery channel cannot cause premature ruptureof the diaphragm. The diaphragm protects the inside contents of thesheath but is sufficiently delicate that passage of the dressing throughthe sheath (even if it is the distal end of the dressing rupturing thediaphragm) does not damage the dressing.

At or prior to introduction at the target tissue site, the sheath distaldiaphragm may be ruptured by the wire body driven passage of the wiredelivery device end and dressing through the diaphragm. This ruptureinitiates exit of dressing outside of the sheath and the expansion ofthe expandable support and dressing once they exit the restrictive spaceof the sheath.

In one embodiment, the expandable support automatically goes into anexpanding format and/or an expanded format upon rupture of the distalend of the sheath. In one embodiment, the sheath may be ruptured whenthe expandable support goes from an unexpanded format into an expandingformat and/or an expanded format. In one embodiment, the sheath may beruptured remotely by triggering a mechanical rupture mechanismassociated with the protective sheath.

Use in Combination with Other Device Components

In some embodiments, the device of the present invention can be used incombination with other device components. For example, the devicedisclosed herein may comprise an annular ring expandable support thatcan be used with another device component having a wire expandablesupport in the form of a stable balloon.

Combining multiple device components can allow for fine control andproper positioning procedures for application of the dressing at atarget tissue site.

Embodiments of Gastrointestinal Delivery Device

FIGS. 11 a-11 c, 12 a, 12 b, 13 a-13 f, 14 a, 14 b, 15 a, and 15 bdepict various aspects of preferred embodiments of the devices describedherein.

FIGS. 11 a-11 c show a schematic drawings side on aspect of the end ofan endoscope used in gastroscopy and different stages of wire deliveryof a preferred delivery method. Chitosan dressing was used in thisembodiment (although dressings can be delivered as well). In FIGS. 11a-11 c , chitosan dressing is bound to an expandable support (6 a-6 c).In the depicted end of the gastroscope, there is a base optic fiberviewing port and a top delivery port that is the distal end of acommunication channel that runs the length of the gastroscope. Deliveryports and channels in gastroscopes are commonly 2.8 mm in diameter andmay also be 3.2 mm in diameter in some specialized gastroscopes. Customgastroscopes may have larger diameter delivery ports and channels butthey are less common.

It is envisioned that the wire delivery device end comprising thechitosan dressing in a compact condition will preferably be able to passdown a 4.0 mm diameter channel, more preferably a 3.2 mm diameterchannel, and most preferably be able to pass down a 2.8 mm diameterdelivery channel to enable the dressing and delivery device of theinvention to be used universally.

FIG. 11 a provides a schematic drawing of a preferred device embodimentcomprising a spring wire tip, preferably formed of ribbon spring wire.In some embodiments, the device comprising a spring wire tip includes:(1) a wire primary support shaft, or support shaft; (2) an articulatedspring locator positioning arm that connects to the wire support shaftat one end, and connecting at the other end; and (3) an expandablesupport that is a ribbon spring annular dressing support. In someembodiments, the device further comprises a chitosan dressing releasablyattached to an expandable support. Inside the gastroscope communicationchannel, the spring locator positioner is z-folded at articulated springhinge points at each of tis proximal and distal ends to overlay thesupport shaft and a tightly furled annular dressing support. The threeparts are aligned along the axis of the communication channel in a tightbundle which is supported by an overlaying thin protective sheath tubewhose end is ruptured on exiting the delivery port. On rupturing, theend of the protective sheath tube, the annular dressing support opensand the spring locator positioner aligns the annular dressing supportorthogonal to the distal exposed primary support shaft. The primarysupport shaft extends the length of the gastroscope channel enabling theoperator to provide the annular dressing support to a bleeding targettissue site, using the visual imaging of the gastroscope viewport andflexibility in the gastroscope tip. Delivery of the dressing using thisapproach requires a second wire (dual wires in the gastroscopecommunication channel) which is described in FIG. 11 b.

FIG. 11 b provides a schematic drawing of another embodiment of thedevice of the present invention. In some embodiments, the expandablesupport is a spring wire tip in the form of a balloon or spring wireframe, that on exiting the distal end of the gastroscope communicationchannel may open (or inflate) into one of an expanding format or anexpanded format to provide a “cushion” end that may also provide adressing attachment location. In some embodiments, the cushion end ofthe expandable support aligns orthogonally with the annular dressingsupport noted above in connection with FIG. 11 a . When used togetherwith the embodiment provided in FIG. 11 a , this alignment provides forhand operated or spring actuated loading centrally onto a chitosandressing supported within the annular dressing frame support on thefirst wire (the spring wire tip in FIG. 11 a ). This loading along thesecond wire tip onto the cushion end provides for release and removal ofthe dressing from the annular support frame by tearing of perforationsat the outer circumference of the dressing and delivery and briefholding (10 to 60 seconds) of the dressing with application of pressureonto the targeted injury site. In this embodiment, the spring wire tipserves as both the expandable support and the wire support shaft.

FIG. 11 c provides a schematic drawing of combined use of theembodiments provided in FIGS. 11 a and 11 b , where the first (FIG. 11 aembodiment) and second wire (FIG. 11 b embodiments) ends appliedtogether with and without a dressing present on the annular dressingsupport.

FIG. 12 a and FIG. 12 b provide two alternate embodiments of wiredelivery of the dressing using only single wire delivery in each. FIG.12 a involves attachment of the dressing to the cushion end of theembodiment provided in FIG. 11 b . FIG. 12 b involves an opening“umbrella style” wire frame with multiple spring wire “umbrella style”spokes that open about 90° and serve as the expandable support on sheathremoval and provide for orthogonal alignment of the dressing in asplayed condition relative to the axis of the gastroscope delivery port.The dressing is sufficiently loosely attached in both alternateembodiments after removal of the protective sheath on exiting thedelivery port that the wet tissue adhesion on placement allows forrelease of the dressing from the delivery end.

FIGS. 13 a-13 f depict preferred embodiments of the delivery deviceformed of an assembly of spring wire expandable support whereby at leastthree corners of the releasable dressing are attached to individual arms(alternatively spokes) of the spring wire. The individual arm attachmentis preferably at articulated dressing tabs radiating from the dressingedge. The tabs may be reinforced which may include, but not be limitedto, localized additional dressing density, additional dressing thicknessand sewn fiber at the tabs and with the reinforcement radiating from thetabs to the dressing center. In some embodiments, the expandable supportcomprises the spring wire arms which are attached to the dressing tabs.The attachment may be achieved through eyelet holes in the tabsaccommodating wire arm ends, by fiber, by glue and by pinched fitting,and other suitable ways. The spring wire assumes its expanding formatand/or expanded format when it is freed from the sheath tube. The outerdiameter of the sheath tubing is sufficiently small to pass down thedelivery channel of the endoscope. The inner diameter of the deliverysheath tubing is sufficiently large to accommodate the folded springwire assembly and the dressing attached to the end of the spring wireassembly. Once freed from its supportive sheath tubing, the spring wirearms enable unfurling of the supported chitosan gastrointestinaldressing, while locating the unfurled dressing orthogonal to the distalend of the endoscope channel ready for deployment on the wound, ortarget tissue site. Release of dressing from the wire delivery devicemay include but not be limited to draw string release, tearingpre-perforated regions of dressing, using localized moisture contact toweaken material in the dressing, and eyelets in corners of the dressingfrom which the delivery wire may be removed away from the target tissuesite once the dressing placed and adhered.

FIG. 13 a depicts the preferred embodiment viewed side-on and with thespring wire in its expanding format and/or expanded format and with fourpoint dressing attachment. FIG. 13 b depicts the preferred embodiment ofFIG. 13 a viewed side-on with the spring wire and dressing in itsunexpanded format and compact condition, respectively, inside the sheathtubing. FIG. 13 c shows the embodiment of FIG. 13 a without an attacheddressing viewed looking along the delivery wire support axis towards thegastroscope delivery port. FIG. 13 d depicts a planar view of a circulardressing with eight folds at 45° to each other and four attachment tabsradiating from the circumference of the dressing and at 90° to oneanother. FIG. 13 e depicts a planar view of a partially folded dressingof FIG. 13 b . FIG. 13 f depicts a planar view of 13 b with wrappedfolding of the 4 fluted fold arms of FIG. 13 e to accommodate thedressing within the narrow confines of the tube sheath.

The following reference identifiers for FIGS. 11 a-11 c, 12 a, 12 b, and13 a-13 f are provided with further narrative description as follows:1—Gastroscope body; 2—Gastroscope delivery port at distal end ofgastroscope communicating channel; 3—Gastroscope optic fiberillumination and viewing port; 4—Primary support wire shaft (a type ofwire support axis); 5—Articulated spring locator positioning arm; with 5a (hidden) as z-folded positioning arm aligned with 4; with 5 b asreleased spring locator positioning arm providing for orthogonalalignment of 6 with 4; 6—dressing support frame (a type of expandablesupport) (represented here as annular but it may include differentshapes); with 6 a furled and aligned with 4; with 6 b released fromalignment with 4 and allowed to unfurl; with 6 c fully unfurled andpresenting its annular face centrally and orthogonally with 4; 7—Thinplastic protective sheath tubing overlying and encompassing the wiredelivery device and chitosan dressing before delivery; 7 a —Alternateshort length thin plastic protective sheath tubing overlying thechitosan dressing before delivery; 8—Expanded view of the folded andcollapsed wire end; 9-9 a shows the collapsed wire tip of the embodimentprovided in FIG. 11 b , that is suitable for use with the embodimentprovided in FIG. 11 a —the dual wire delivery method; 9 b shows theexpanded wire tip of the embodiment provided in FIG. 11 b that expandson exiting the distal end of the delivery tube; 9 c provides a cushionedend formed of expanded spring wire frame or inflated and directionalstable balloon (different types of expandable support) that loads thedressing supported in 6 c to provide for its detachment and applicationon an injury site; 10 shows the dressing, e.g. chitosan dressing(represented here as round in shape, however it's shape may includedifferent shapes including, but not limited to, circular, circular andpetal-shaped, triangular, square, rectangular, pentagonal, hexagonal andoctagonal); 10 a shows a perforated circumference of the dressing toprovide for release from the annular support frame 6 on application of 9c orthogonal to the dressing face; 10—shows the chitosan dressing indifferent states: either folded/furled or unfolded/unfurled, and eitherinside a protective sheath or not within a protective sheath; 11—wiresupport axis in alignment with gastroscope delivery channel axis actingas a delivery shaft and support for umbrella style dressing delivery;12—Wire spring spokes of the umbrella (expandable support) that openabout 90° relative to 11 on release from the protective sheath 7 and actin concert to present the dressing orthogonal to 11; 13—wire device bodythat conforms to endoscope delivery channel inside tubing sheath withdistal end supporting sprung delivery wire and dressing; 14—articulatedspring arms that together act as the wire support axis 11;15—articulated spring arms connecting 14 to the dressing 10; 16—articulated base support spring struts (expandable support) thatconnect ends of 15 together and, when released from 7, provides for basedressing support loading against injury site and together with 15provide for 12; 17—tab attachment points to 15 (and 12); 18—extremitywire ends of wire delivery device to attach to folded back dressing tabattachment points.

The delivery systems illustrated in FIGS. 11 a-11 c, 12 a, 12 b, and 13a-13 f can be described in other ways. For example, the delivery systemillustrated in FIG. 11 a may include an outer sheath 1, which may be anouter sheath of an endoscope such as a gastroscope. The outer sheath 1may have a first opening or port 2 at a distal end thereof, throughwhich a wire or other support shaft 4 may extend. The outer sheath 1 mayhave a second opening or port 3 at the distal end thereof, which canfunction as an eyepiece to allow an operator to view operation of thesupport shaft 4 and other components coupled thereto. The deliverysystem illustrated in FIG. 11 a may also include the support shaft 4,which can be extended distally or retracted proximally, and/or rotatedwith respect to the outer sheath 1. Thus, a distal end portion of thesupport shaft 4 can be surrounded and protected by the outer sheath 1while the delivery system is inserted into a patient's body, and thedistal end portion of the support shaft 4 can be moved outside of theouter sheath 1 through the port 2 for use once the delivery system hasbeen inserted into a patient's body.

The delivery system illustrated in FIG. 11 a also includes a positioningarm 5 b that may be coupled, such as rigidly and/or integrally coupled,to a distal end of the support shaft 4. When the delivery systemillustrated in FIG. 11 a is in a fully deployed configuration, thepositioning arm 5 b may be coupled to the distal end of the supportshaft 4 at an oblique angle, so that the positioning arm 5 b extendsboth longitudinally, in a direction aligned with the distal end of thesupport shaft 4, and radially, in a direction transverse to the distalend of the support shaft 4. The delivery system illustrated in FIG. 11 aalso includes a support frame 6, identified in different configurationsin FIG. 11 a by reference numerals 6 a, 6 b, and 6 c. The support frame6 may be coupled, such as rigidly and/or integrally coupled, to a distalend of the positioning arm 5 b. When the delivery system illustrated inFIG. 11 a is in a fully deployed configuration, the support frame 6 maycomprise a circular piece of wire or other material, and may be coupledto the distal end of the positioning arm 5 b at an angle such that itscircular shape is oriented perpendicular to the distal end portion ofthe support shaft 4.

The delivery system illustrated in FIG. 11 a also includes an innersheath that is located inside the outer sheath 1 and that extends aroundand protects at least the distal end portion of the support shaft 4, thepositioning arm 5 b, and the support frame 6. As illustrated in FIG. 11a , the delivery system may include a relatively short inner sheath 7 athat covers a relatively small distal end portion of the support shaft4, the positioning arm 5 b, and the support frame 6, or the deliverysystem may include a relatively long inner sheath 7 that covers anentirety of or a relatively long distal end portion of the support shaft4, the positioning arm 5 b, and the support frame 6.

FIG. 11 b illustrates that the delivery system of FIG. 11 a may alsoinclude a balloon 9, portions of which are identified in differentconfigurations in FIG. 11 b by reference numerals 9 a, 9 b, and 9 c. Theballoon 9 may extend out of the first port 2 at the distal end of theouter sheath 1. The balloon 9 can be extended distally or retractedproximally with respect to the outer sheath 1. Thus, the balloon 9 canbe deflated and surrounded and protected by the outer sheath 1 while thedelivery system is inserted into a patient's body, and the balloon 9 canbe moved outside of the outer sheath 1 through the port 2 and inflatedfor use once the delivery system has been inserted into a patient'sbody. FIG. 11 c illustrates the delivery system of FIG. 11 a with boththe support shaft 4 and the balloon 9 extending out of the first port 2at the distal end of the outer sheath 1 at the same time, orsimultaneously or concurrently. In such embodiments, the inner sheaththat encloses the components as described above may also enclose theballoon 9, or the delivery system may include a second inner sheathdistinct from the inner sheath described above, that encloses theballoon 9. FIG. 11 c also illustrates that a dressing 10 having agenerally circular shape may be mounted to the support frame and mayspan across a circular opening of the circular support frame 6.

To assemble and prepare the delivery system of FIGS. 11 a-11 c for use,an operator may begin with the delivery system in the configurationillustrated in the upper portion of FIG. 11 c . The operator may thendeflate the balloon 9. The operator may then couple the dressing 10 tothe support frame 6 such that the dressing 10 spans across the circularopening of the circular support frame 6 in accordance with thedescription of such features provided elsewhere herein. The dressing 10,the support frame 6, and the positioning arm 5 b may then be folded up,such as so that the positioning arm 5 b is bent backwards and lays flushagainst the distal end portion of the support shaft 4. The distal endportion of the support shaft 4, the positioning arm 5 b, the supportframe 6, and/or the deflated balloon 9 can then be positioned within aninner sheath such as the inner sheath 7 or the inner sheath 7 a. Suchcomponents can then be retracted with respect to the outer sheath 1until they are inside of, and covered and protected by, the outer sheath1.

To use the delivery system of FIGS. 11 a-11 c , an operator such as aphysician may insert the outer sheath 1, which may be an outer sheath ofan endoscope such as a gastroscope, into a patient's body, such asthrough the patient's mouth and into the patient's stomach. Once thedistal end of the outer sheath 1 is located at a desired position withina patient's body, such as in the patient's stomach, the operator canmove the balloon 9 and support shaft 4 distally with respect to theouter sheath 1. In some cases, while the operator does so, the innersheath remains stationary, and moving the support shaft 4 distallypunctures or ruptures the distal end of the inner sheath so that thedistal end portion of the support shaft 4 and other associatedcomponents, including the balloon 9, can extend distally out of both theouter sheath 1 and the inner sheath.

As the support shaft 4 moves distally with respect to the outer andinner sheaths in this manner, the positioning arm 5 b and the supportframe 6 are released and are allowed to unfold with respect to oneanother within the patient's body. The operator can then view theposition of such components, and of the dressing 10, through theeyepiece 3, and can move the support shaft 4 along the length of theouter sheath 1, and/or rotate the support shaft 4 with respect to andabout the length of the outer sheath 1, so as to position the dressing10 at a desired location, for example, such that a first side of thedressing 10 lies against an internal wall of an internal lumen insidethe patient's body, such as a wall of the patient's stomach. Once thedressing 10 has been desirably positioned in this manner, the operatorcan inflate the balloon 9 and position the balloon 9 adjacent to and inabutting contact with a second side of the dressing 10 opposite thefirst side thereof, and can urge the inflated balloon to press againstthe second side of the dressing 10. In this manner, the dressing 10 maybe pressed against the wall of a lumen inside the patient's body,thereby causing the dressing 10 to stick to the wall in accordance withthe description of such features provided elsewhere herein.

Once the dressing 10 has been pressed against the wall, the dressing 10can be released from the support frame 6 in accordance with thedescription of such features provided elsewhere herein. The balloon 9can then be deflated and retracted longitudinally and proximally intothe outer sheath 1. The support shaft 4 can then be retractedlongitudinally and proximally into the outer sheath 1. In some cases,retracting the support shaft 4 into the outer sheath 1 can automaticallyinduce the positioning arm 5 b and/or the support frame 6 to fold up asthey are pulled into the outer sheath 1 through the first port 2. Theouter sheath 1, and the endoscope or gastroscope of which it is a part,can then be retracted out of the patient, such as out of the patient'sstomach through the patient's mouth.

As another example, the delivery system illustrated in FIG. 12 a mayinclude an outer sheath 1, which may be an outer sheath of an endoscopesuch as a gastroscope. The outer sheath 1 may have a first opening orport 2 at a distal end thereof, through which a balloon 9, identified inthe drawings in deflated and inflated configurations as 9 a and 9 b,respectively, may extend. The outer sheath 1 may have a second openingor port 3 at the distal end thereof, which can function as an eyepieceto allow an operator to view operation of the balloon 9 and othercomponents coupled thereto. The delivery system illustrated in FIG. 12 amay also include the balloon 9, which can be extended distally orretracted proximally, and/or rotated with respect to the outer sheath 1.Thus, a distal end portion of the balloon 9 can be surrounded andprotected by the outer sheath 1 while the delivery system is insertedinto a patient's body, and the distal end portion of the balloon 9 canbe moved outside of the outer sheath 1 through the port 2 for use oncethe delivery system has been inserted into a patient's body.

The delivery system illustrated in FIG. 12 a can omit, or not include,and function without, the support shaft 4, the positioning arm 5 b,and/or the support frame 6 illustrated in FIGS. 11 a-11 c . FIG. 12 aalso illustrates that a dressing 10 having a generally circular shapemay be mounted to the balloon 9 and may span across a circular orgenerally dome-shaped distal end portion of the balloon 9 when theballoon 9 is in an inflated configuration. The delivery systemillustrated in FIG. 12 a also includes an inner sheath 7 that is locatedinside the outer sheath 1 and that extends around and protects at leastthe distal end portion of the balloon 9.

To assemble and prepare the delivery system of FIG. 12 a for use, anoperator may begin with the delivery system in the configurationillustrated in the lower portion of FIG. 12 a . The operator may thencouple the dressing 10 to the balloon 9, such as to a generallydome-shaped distal end portion of the balloon 9. The operator may thendeflate the balloon 9, and as the balloon 9 deflates, the dressing 10may be folded up, such as in accordance with related descriptionprovided elsewhere herein. The distal end portion of the balloon 9 andthe folded-up dressing 10 can then be positioned within the inner sheath7. Such components can then be retracted with respect to the outersheath 1 until they are inside of, and covered and protected by, theouter sheath 1.

To use the delivery system of FIG. 12 a , an operator such as aphysician may insert the outer sheath 1, which may be an outer sheath ofan endoscope such as a gastroscope, into a patient's body, such asthrough the patient's mouth and into the patient's stomach. Once thedistal end of the outer sheath 1 is located at a desired position withina patient's body, such as in the patient's stomach, the operator canmove the balloon 9 distally with respect to the outer sheath 1. In somecases, while the operator does so, the inner sheath 7 remainsstationary, and moving the balloon 9 distally punctures or ruptures thedistal end of the inner sheath 7 so that the distal end portion of theballoon 9 and other associated components, including the dressing 10,can extend distally out of both the outer sheath 1 and the inner sheath7.

Once the balloon 9 is moved distally with respect to the outer and innersheaths 1, 7 in this manner, the operator can inflate the balloon 9. Theoperator can then move the balloon 9 longitudinally, such as distally orproximally, and/or rotate the balloon 9, with respect to the outersheath 1, while keeping the outer sheath 1 stationary, to position thedressing 10 at a desired location. The operator can then view theposition of such components through the eyepiece 3, and can continue tomove and/or rotate the balloon 9 with respect to the outer sheath 1 soas to position the dressing 10 at a desired location, for example, suchthat a side of the dressing 10 opposite the balloon 9 lies against aninternal wall of an internal lumen inside the patient's body, such as awall of the patient's stomach. Once the dressing 10 has been desirablypositioned in this manner, the operator can urge the inflated balloon 9to press the side of the dressing 10 into the wall. In this manner, thedressing 10 may be pressed against the wall of a lumen inside thepatient's body, thereby causing the dressing 10 to stick to the wall inaccordance with the description of such features provided elsewhereherein.

Once the dressing 10 has been pressed against the wall, the dressing 10can be released from the balloon 9 in accordance with the description ofsuch features provided elsewhere herein. The balloon 9 can then bedeflated and retracted longitudinally and proximally into the outersheath 1. The outer sheath 1, and the endoscope or gastroscope of whichit is a part, can then be retracted out of the patient, such as out ofthe patient's stomach through the patient's mouth.

As another example, the delivery system illustrated in FIG. 12 b mayinclude an outer sheath 1, which may be an outer sheath of an endoscopesuch as a gastroscope. The outer sheath 1 may have a first opening orport 2 at a distal end thereof, through which a support wire 11 mayextend. The outer sheath 1 may have a second opening or port 3 at thedistal end thereof, which can function as an eyepiece to allow anoperator to view operation of the support wire 11 and other componentscoupled thereto. The delivery system illustrated in FIG. 12 b may alsoinclude the support wire 11, which can be extended distally or retractedproximally, and/or rotated with respect to the outer sheath 1. Thus, adistal end portion of the support wire 11 can be surrounded andprotected by the outer sheath 1 while the delivery system is insertedinto a patient's body, and the distal end portion of the support wire 11can be moved outside of the outer sheath 1 through the port 2 for useonce the delivery system has been inserted into a patient's body.

The delivery system illustrated in FIG. 12 b also includes a pluralityof wire support arms 12 that may be coupled, such as rigidly and/orintegrally coupled, to a distal end of the support wire 11. When thedelivery system illustrated in FIG. 12 b is in a fully deployedconfiguration, the support arms 12 may be coupled to the distal end ofthe support wire 11 at oblique and/or right angles, so that the supportarms 12 extend either both longitudinally, in a direction aligned withthe distal end of the support wire 11, and radially, in a directiontransverse to the distal end of the support wire 11, or purely radially,in the direction transverse and perpendicular to the distal end of thesupport wire 11.

The delivery system illustrated in FIG. 12 b also includes an innersheath that is located inside the outer sheath 1 and that extends aroundand protects at least the distal end portion of the support wire 11 andthe support arms 12. As illustrated in FIG. 12 b , the delivery systemmay include a relatively short inner sheath 7 a that covers a relativelysmall distal end portion of the support wire 11 and the support arms 12,or the delivery system may include a relatively long inner sheath 7 thatcovers an entirety of or a relatively long distal end portion of thesupport wire 11 and the support arms 12. FIG. 12 b also illustrates thata dressing 10 having a generally circular shape may be mounted to thesupport arms 12 and may span across a distal end portion of the deliverysystem. In some cases, an overall shape of the distal end portion of thedelivery system may be defined by the outer terminal ends of the supportarms 12, and may have an approximately circular shape.

To assemble and prepare the delivery system of FIG. 12 b for use, anoperator may begin with the delivery system in the configurationillustrated in the lower portion of FIG. 12 b . The operator may thencouple the dressing 10 to the support arms 12 such that the dressing 10spans across the generally circular shape of the distal end of thedelivery system in accordance with the description of such featuresprovided elsewhere herein. The dressing 10 and the support arms 12 maythen be folded up, such as so that the support arms 12 are bentbackwards and lay flush against the distal end portion of the supportwire 11. The distal end portion of the support wire 11, the support arms12, and the dressing 10 can then be positioned within an inner sheathsuch as the inner sheath 7 or the inner sheath 7 a. Such components canthen be retracted with respect to the outer sheath 1 until they areinside of, and covered and protected by, the outer sheath 1.

To use the delivery system of FIG. 12 b , an operator such as aphysician may insert the outer sheath 1, which may be an outer sheath ofan endoscope such as a gastroscope, into a patient's body, such asthrough the patient's mouth and into the patient's stomach. Once thedistal end of the outer sheath 1 is located at a desired position withina patient's body, such as in the patient's stomach, the operator canmove the support wire 11 distally with respect to the outer sheath 1. Insome cases, while the operator does so, the inner sheath remainsstationary, and moving the support wire 11 distally punctures orruptures the distal end of the inner sheath so that the distal endportion of the support wire 11 and other associated components canextend distally out of both the outer sheath 1 and the inner sheath.

As the support wire 11 moves distally with respect to the outer andinner sheaths in this manner, the support arms 12 are released and areallowed to unfold with respect to one another within the patient's body.The operator can then view the position of such components, and of thedressing 10, through the eyepiece 3, and can move the support wire 11along the length of the outer sheath 1, and/or rotate the support wire11 with respect to and about the length of the outer sheath 1, so as toposition the dressing 10 at a desired location, for example, such that aside of the dressing 10 lies against an internal wall of an internallumen inside the patient's body, such as a wall of the patient'sstomach. Once the dressing 10 has been desirably positioned in thismanner, the operator can urge the support wire 11 to press the dressing10 against the wall of the lumen inside the patient's body, therebycausing the dressing 10 to stick to the wall in accordance with thedescription of such features provided elsewhere herein.

Once the dressing 10 has been pressed against the wall, the dressing 10can be released from the support arms 12 in accordance with thedescription of such features provided elsewhere herein. The support wire11 can then be retracted longitudinally and proximally into the outersheath 1. In some cases, retracting the support wire 11 into the outersheath 1 can automatically induce the support arms 12 to fold up as theyare pulled into the outer sheath 1 through the first port 2. The outersheath 1, and the endoscope or gastroscope of which it is a part, canthen be retracted out of the patient, such as out of the patient'sstomach through the patient's mouth.

As another example, the delivery system illustrated in FIGS. 13 a-13 fmay include an outer sheath 13, which may be an outer sheath of anendoscope such as a gastroscope. The outer sheath 13 may have a firstopening or port at a distal end thereof, through which a plurality ofsupport wires 14, 15 may extend. In the embodiment illustrated in FIGS.13 a-13 f , the plurality of support wires 14, 15 includes exactly foursupport wires 14, 15, but in other embodiments, the plurality of supportwires 14, 15 may include any suitable number of support wires 14, 15,such as exactly three, five, six, seven, eight, nine, ten, twelve,fifteen, or more support wires 14, 15. The outer sheath 13 may have asecond opening or port at the distal end thereof, which can function asan eyepiece to allow an operator to view operation of the support wires14, 15 and other components coupled thereto. The delivery systemillustrated in FIGS. 13 a-13 f may also include the support wires 14,15, which can be extended distally or retracted proximally, and/orrotated with respect to the outer sheath 13. Thus, distal end portionsof the support wires 14, 15 can be surrounded and protected by the outersheath 13 while the delivery system is inserted into a patient's body,and the distal end portions of the support wires 14, 15 can be movedoutside of the outer sheath 13 through the port for use once thedelivery system has been inserted into a patient's body.

As illustrated in FIGS. 13 a and 13 c , when the delivery system ofFIGS. 13 a-13 f is in a deployed configuration, each of the supportwires 14, 15 has a proximal portion 14 that extends out of the port atthe distal end of the outer sheath 13, and a distal portion 15 thatextends from the proximal portion 14 to the distal end of the supportsystem. The distal portion 15 may be coupled to, such as rigidly and/orintegrally coupled to, the proximal portion 14 at an angle and at ajoint. As further illustrated in FIGS. 13 a and 13 c , the proximalportions 14 extend at oblique angles with respect to the distal endportion of the outer sheath 13, so that the proximal portions 14 extendboth longitudinally, in a direction aligned with the distal end portionof the outer sheath 13, and radially, in a direction transverse to thedistal end portion of the outer sheath 13. As further illustrated inFIGS. 13 a and 13 c , the distal portions 15 also extend at obliqueangles with respect to the distal end portion of the outer sheath 13, sothat the distal portions 15 extend both longitudinally, in a directionaligned with the distal end portion of the outer sheath 13, andradially, in a direction transverse to the distal end portion of theouter sheath 13. As illustrated in FIG. 13 a , the oblique angle betweenthe orientation of the distal portions 15 and the distal end portion ofthe outer sheath 13 is greater than the oblique angle between theorientation of the proximal portions 14 and the distal end portion ofthe outer sheath 13.

The delivery system illustrated in FIGS. 13 a-13 f also includes aplurality of wire support arms 16 that may be coupled, such as rigidlyand/or integrally coupled, to distal ends of the distal portions 15 ofthe support wires 14, 15, such as at attachment locations or points 17,18. When the delivery system illustrated in FIGS. 13 a-13 f is in afully deployed configuration, the support arms 16 may be coupled to thedistal ends of the support wires 14, 15 at oblique angles so that thesupport arms 16 extend purely radially, in a direction transverse andperpendicular to the distal end portion of the outer sheath 13.

As illustrated in FIG. 13 b , the delivery system illustrated in FIGS.13 a-13 f also includes an inner sheath 7 that is located inside theouter sheath 13 and that extends around and protects at least the distalend portion of the support wires 14, 15 and the support arms 16. FIG. 13b also illustrates that a dressing 10 having a generally circular shapemay be mounted to the support arms 16 and may span across a distal endportion of the delivery system. In some cases, an overall shape of thedistal end portion of the delivery system may be defined by the outer,terminal ends of the support arms 16, and may have an approximatelycircular shape.

To assemble and prepare the delivery system of FIGS. 13 a-13 f for use,an operator may begin with the delivery system in the configurationillustrated in the side and end views of FIGS. 13 a and 13 c . Theoperator may then couple the dressing to the support arms 16, such as atthe attachment locations 17, 18, and such that the dressing 10 spansacross the generally circular shape of the distal end of the deliverysystem in accordance with the description of such features providedelsewhere herein, as illustrated in FIG. 13 d . The dressing 10, thesupport arms 16, and the support wires 14, 15 may then be folded up,such as so that the support wires 14, 15 extend generally linearly andthe angle between their proximal portions 14 and their distal portions15 is approximately zero, such as so that the support arms 16 are bentbackwards and extend proximally, and lay flush against the distal endportions 15 of the support wires 14, 15, and such that the dressing 10is folded up and extends distally with respect to the distal ends of thesupport wires 14, 15, and of the support arms 16, as illustrated in FIG.13 b.

As illustrated in FIG. 13 d , the dressing may have an overall circularshape and four fold lines, each of which extends along a diameter of thecircle and through the center of the circle, and which together evenlydivide the circular shape into eight equal-area segments of the overallcircular shape. As illustrated in FIG. 13 e , as the dressing 10 foldsup, the dressing 10 folds along all four of the fold lines, folding toform peaks along two perpendicular fold lines and valleys along theother two perpendicular fold lines when viewed on-end, thus, forming ashape generally resembling a four-point compass rose. As the dressing 10folds up in this manner, the dressing 10 eventually forms fourdual-layered arms that extend radially outward from a centerline of thedelivery system. As illustrated in FIG. 13 f , once the dressing 10folds up in this manner, the four arms of the dressing can be wrapped ina spiral configuration about the rest of the delivery system to reducethe overall profile of the delivery system. Distal end portions of thesupport wires 14, 15, the support arms 16, and the dressing 10 can thenbe positioned within an inner sheath 7, as illustrated in FIG. 13 b .Such components can then be retracted with respect to the outer sheath13 until they are inside of, and covered and protected by, the outersheath 13.

To use the delivery system of FIGS. 13 a-13 f , an operator such as aphysician may insert the outer sheath 13, which may be an outer sheathof an endoscope such as a gastroscope, into a patient's body, such asthrough the patient's mouth and into the patient's stomach. Once thedistal end of the outer sheath 13 is located at a desired positionwithin a patient's body, such as in the patient's stomach, the operatorcan move the support wires 14, 15 distally with respect to the outersheath 13. In some cases, while the operator does so, the inner sheath 7remains stationary, and moving the support wires 14, 15 distallypunctures or ruptures the distal end of the inner sheath 7 so that thedistal end portion of the support wires 14, 15 and other associatedcomponents can extend distally out of both the outer sheath 13 and theinner sheath 7.

As the support wires 14, 15 move distally with respect to the outer andinner sheaths in this manner, the distal portions 15 are allowed tounfold with respect to the proximal portions 14, and the support arms 16are released and are allowed to unfold with respect to one anotherwithin the patient's body. The operator can then view the position ofsuch components, and of the dressing 10, through the eyepiece, and canmove the support wires 14, 15 along the length of the outer sheath 13,and/or rotate the support wires 14, 15 with respect to and about thelength of the outer sheath 13, so as to position the dressing 10 at adesired location, for example, such that a side of the dressing 10 liesagainst an internal wall of an internal lumen inside the patient's body,such as a wall of the patient's stomach. Once the dressing 10 has beendesirably positioned in this manner, the operator can urge the supportwires 14, 15 to press the dressing 10 against the wall of the lumeninside the patient's body, thereby causing the dressing 10 to stick tothe wall in accordance with the description of such features providedelsewhere herein.

Once the dressing 10 has been pressed against the wall, the dressing 10can be released from the support arms 16 in accordance with thedescription of such features provided elsewhere herein. The supportwires 14, 15 can then be retracted longitudinally and proximally intothe outer sheath 13. In some cases, retracting the support wires 14, 15into the outer sheath 13 can automatically induce the support wires 14,15, and the support arms 16 to fold up as they are pulled into the outersheath 13 through the port. The outer sheath 13, and the endoscope orgastroscope of which it is a part, can then be retracted out of thepatient, such as out of the patient's stomach through the patient'smouth.

FIGS. 14 a and 14 b illustrate side and end views, respectively, of awire-based delivery system similar to that illustrated in FIGS. 13 a-13f , and that is operated and functions in a manner similar to thatdescribed above for the system illustrated in FIGS. 13 a-13 f . Thedelivery system of FIGS. 14 a and 14 b differs from that of FIGS. 13a-13 f in that it includes a central interlocking loop restrictioncoupled to the support arms 16 (which may also be referred to as“dressing support struts”) and doesn't include the tabs described aboveat the attachment locations 17, 18 (which may also be referred to as“wire looping of the corners”). FIGS. 15 a and 15 b illustrate side andend views, respectively, of another wire-based delivery system similarto those illustrated in FIGS. 13 a-13 f, 14 a, and 14 b , and that isoperated and functions in a manner similar to that described above forthe systems illustrated in FIGS. 13 a-13 f, 14 a, and 14 b . In someimplementations, components of the delivery system illustrated in FIGS.15 a and 15 b may be laser cut from larger pieces of material.

A preferred delivery system for the chitosan gastrointestinal hemostaticdressing (CGHD) comprises wire delivery (WD). In such a system, insidethe delivery channel of the endoscope, the CGHD is present as a furledor folded and compacted dressing, i.e., in its compact condition, thatis attached to an expandable support having a wire tip with springmemory. It is preferred that that the CGHD in its compact condition isconstrained within a closely fitting, moisture resistant, thin-walled,protective tubing sheath. The closely fitting tubing sheath alsoprovides so that the expandable support wire tip and CGHD in its compactcondition are covered by the sheath and fit within and slide through thebore of the endoscope delivery channel to be delivered to a targettissue site by projecting the expandable support and dressing throughand out of the distal end of tubing sheath. Preferably, the distal endof the tubing sheath is sealed with a delicate protected membrane thatis ruptured on projection of the expandable support and dressing throughand out of the distal end of tubing sheath. On exiting the endoscopedelivery channel for application to a target tissue site, the expandablesupport in its unexpanded format and the dressing in its compactcondition are freed from the sheath, the expandable support havingspring memory that is now unconfined by the sheath and/or endoscopedelivery channel, transitions into its expanding format and/or itsexpanded format and the dressing transitions into its transitioncondition and/or its splayed condition. As the wire tip expandablesupport springs open, the dressing, preferably a CGHD, is positioned toallow its application to the target tissue site with a pressureapplication of, for example, about 100 g/cm² and with an applicationtime of, for example, up to about 30 seconds or up to about 60 seconds.On removal of the expandable support wire tip from the wound, thedressing, preferably a CGHD, is left in place and adhered uniformly tothe target tissue site to provide hemostasis and wound protection.

This exemplary WD design provides an expandable support with spring wiretips in a flat or, alternatively, a circular wire profile that can betightly folded into and unexpanded format and which can spring quicklyback to an original unfolded state, or expanded format, upon release ofphysical constraint such as removal of the outer sheath protectionand/or exit from the endoscope working channel. A secondary WD springwire or an alternative inflated balloon pressure applicator end may beincluded with the primary WD to provide a cushion delivery design behindthe dressing, preferably a CGHD, attached to the primary WD. That is,the secondary WD applicator “cushion” is formed either from theinterconnected spring wire or inflatable balloon or bladder whichsprings into its inflated cushion shape on exiting the delivery tube andis used to apply uniform pressure orthogonally and centrally behind thedressing, preferably a CGHD, and primary WD upon its application to theinjury. It is not depicted here, but the primary WD applicator wiredelivery body connecting to the proximal end of the delivery channel isformed of a tube through which the secondary device can be passed. Thesecondary WD applicator may be used to detach the dressing fromperforated attachment points on the primary support shaft.

Chitosan Dressing; and its Production

In certain embodiments, the chitosan dressing comprising a catecholmodified chitosan, wherein the dressing is hemostatic and has athickness that is 500 microns or less. The dressing may have a drydressing thickness that is one of: (i) about 200 microns or less; (ii)about 100 microns or less; or (iii) about 50 microns or less. Thedressing may have a density that is in the range of about 0.03 g/cm³ toabout 0.7 g/cm³, in the range of: (i) about 0.3 g/cm³ to about 0.4g/cm³; (ii) about 0.4 g/cm³ to about 0.5 g/cm³, or in the range of about0.35 g/cm³ to about 0.55 g/cm³. The dressing may be compressed. Thedressing may be square, rectangular, circular, or circular petal shapedand measurements, for each of the length and width for a square orrectangular shape, may range from about 10 mm to about 50 mm, or for acircular or circular petal shape from about 10 mm to about 50 mm indiameter. In certain embodiments, the dressing measures as one of: (i)10 mm by 10 mm; (ii) 20 mm by 20 mm; or (iii) 25 mm by 25 mm. Thedressing, when dry, has a moisture content of: (1) 15% or less by weight(w/w); (2) 8% or less by weight (w/w); or (3) 4% or less by weight(w/w). The dressing may have an adhesive side and a non-adhesive side.The dressing may have an adhesive side provided on a first layer and anon-adhesive side is provided on a second layer. The adhesive side ofthe dressing adheres to a tissue surface when the dressing is wet. Thenon-adhesive side of the dressing does not adhere to a delivery devicewhen the dressing is wet. The dressing can adhere to a gastrointestinalmucosa in 1 minute or less. The dressing can form a quaternary ammoniumcation at the chitosan glucosamine C-2 amine at a tissue site. Thedressing may comprise catechol oxidized to o-quinone and cross-linked inthe chitosan dressing. The chitosan dressing may have a browncoloration, including a dark brown coloration. In one embodiment, thedressing may comprise catechol that is not oxidized, and wherein thechitosan dressing has a pink coloration. The dressing may comprisefreeze-dried lamella. The dressing may comprise a freeze-dried structurehas a thickness of 50 microns or less. The dressing may comprise afreeze-dried structure that includes more than one freeze-dried layer.The dressing may comprise spun fibers. The dressing may comprise aporous surface. The dressing may comprise a porous surface wherein theporous surface provides one or more of: (i) and absorbent surface; and(ii) channels to redirect moisture away from a target tissue surfacesite. The dressing may adhere to wet tissue when in a wet condition. Thedressing adherence strength may be greater than or equal to about 1 kPa.The dressing resists dissolution in water, saline solution, blood, or GIfluid at about 37° C. for at least about 6 hours. The dressing can befolded or furled without cracking or tearing. The dressing may, in anopen, unfurled, or unfolded condition, have an outward facing surfacearea that is one of about six times greater, about five times greater,or about four times greater than the outward facing surface area of thatsame dressing when it is in a closed, furled, or folded condition. Thedressing may have a ratio of the outward facing surface area of an open,unfurled, or unfolded condition relative to a closed, furled, or foldedcondition that is about 15:1, or about 14:1, or about 13:1, or about12:1, or about 11:1, or about 10:1, or about 9:1, or about 8:1, or about7:1, or about 6:1, or about 5:1, or about 4:1, or about 3:1, or about2:1. The dressing can be punctured or sewn without cracking or tearing.The dressing can be cross-linked. The dressing is able to be deliveredintact by a balloon device, a wire device, or an endoscopic device,wherein said device may comprise a working channel having a diameter of3.2 mm or less, and wherein the dressing is delivered through theworking channel. The dressing is able to wet and adhere intact togastric mucosa in less than 30 seconds with application of lightpressure, e.g., about 200-300 g. The dressing is able to removehydrophilic and hydrophobic biological fluids that can interfere withadhesion. The dressing is able to stay in place intact and stop moderateto oozing bleeding ranging from between about 20 ml/min to about 100ml/min. The dressing readily detaches from a delivery device afteradherence to a target tissue site. The dressing is able to resistdissolution for at least six hours after adhering to an injury site inpresence of corrosive enzymes and acid environment of about pH 3. Thedressing is able to seal and protect a target tissue site for at least12 hours. The dressing is able to achieve a controlled, slow dissolutionfrom the attachment site over a period of time not exceeding seven (7)days. The dressing is able to be folded and unfolded. The dressing isable to be furled and unfurled. The dressing is not readily soluble inwater, saline solution, blood, or GI fluid at about 37° C. for at least12 hours following application. The dressing is not readily soluble inwater, saline solution, blood, or GI fluid at about 37° C. for at least24 hours following application. The dressing does not adhere to adelivery device. The dressing does not does not increase or decrease insize by more than about 25% in length and width, or more than about 50%in thickness in the presence of water, saline solution, blood, or GIfluid at about 37° C. The dressing comprises an adhesive side thatinteracts with an injury site, and wherein the chitosan dressingcomprises a non-adhesive side that interacts with one of a deliverydevice or the adhesive side when the dressing is in a dry and folded ora dry and furled condition. The dressing is capable of being terminallysterilized without affecting dressing characteristics. The chitosandressing is capable of being stored under controlled conditions overtime without affecting dressing characteristics.

In some embodiments, the dressing can be used for treatment of adisease, condition, disorder, trauma, or injury. For example, the use ofthe dressing in the treatment of a disease, condition, disorder, trauma,or injury, comprising directly adhering the dressing at an injury siteupon wetting, and applying pressure to the dressing for about 30seconds. The dressing for use in treatment of a disease, condition,disorder, trauma, or injury, may remove hydrophilic and hydrophobicbiological fluids upon adherence. The dressing for use in treatment of adisease, condition, disorder, trauma, or injury, may comprise leavingthe dressing in place at a target tissue site and the dressing mayremain at the target tissue site for at least 24 hours. The dressing foruse in treatment of a disease, condition, disorder, trauma, or injury,may be capable of slow dissolution at the target tissue site anddissolves completely without human intervention in seven days or less.

In some embodiments, the invention disclosed herein comprises methods ofproducing the chitosan dressing. In one embodiment, the methodcomprises: performing synthesis with chitosan and catechol in an aqueousreaction solution; maintaining a pH of the reaction solution at or belowpH 5.5; increasing the pH of the reaction solution, and controllingoxygen exposure to the reaction solution, to provide catechol oxidationand cross-linking; and drying the reaction solution. In certainembodiments, the methods do not comprise an intermediate drying stepbetween step. In certain embodiments, the methods comprise increasingthe pH of the reaction solution from about 5.8 to about 6.2. Anotherembodiment of a method of producing the chitosan dressing comprises amethod of producing a chitosan dressing comprising: freeze-drying afirst aqueous solution comprising chitosan; freeze-drying a secondaqueous solution comprising chitosan; obtaining a low-density chitosandressing with inter-connected porous structure from each of the abovesteps; and compressing the low-density chitosan dressing from each ofsteps; and preparing a two-layer chitosan dressing from the compressedlow-density chitosan dressing. In certain embodiments, the low-densitychitosan dressings from each of above-mentioned freeze-drying steps arecombined prior to compression. In certain embodiments, the compressingof step may occur at temperature ranging from about 20° C. to about 150°C. In certain embodiments, the dressing is dried to a moisture contentof less than about 15% (w/w).

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

EXAMPLES Example 1

In the development of the chitosan gastrointestinal hemostatic dressing(CGHD) of the invention different prototype dressing compositions wereinvestigated to prepare foldable, mucoadhesive and cohesive chitosandressings with sustained hemostatic efficacy at pH close to 4. Such thinhigh-surface area hemostatic dressings which are uniquely well-suitedfor use in extreme physiological environments, including (but notlimited to) the stomach and other parts of the GI tract, and capable ofdelivery using minimally invasive techniques due to their small volumerelative to strength and treatment surface area capacity, have not beenpreviously described. There is an urgent need for such dressings. TheCGHD dressings disclosed herein defied conventional expectations as towhat may be expected from, or achieved using, chitosan based materialsto form hemostatic, thin, high surface area, low volume, foldable,strong, low pH dissolution resistant, adherent, biocompatible dressings.

CGHD formulations were assessed in vitro for long-term, mechanicalresilience, ability to be delivered, low pH/wet adherence, hemostaticability and ability to be left in place, and to be digested or dissolvedin less than 168 hours, or one week (7 days). Prototypes were screenedin an acute stomach injury model before down selection to bestperforming dressings for ≥3 hour application control of non-varicealupper gastrointestinal bleeding (UGIB). In vivo swine models of gastricarterial bleeding were used to assess acute and prolonged (≥3 hours)control of brisk (class 2A) non-variceal UGIB.

The following materials were used in the gastrointestinal chitosanhemostatic dressing development:

-   -   Chitosan A: Primex ChitoClear 65010, TM 4375, MW=250-300 kDa,        Brookfield viscosity in 1.0% w/w chitosan solution in 1.0%        acetic acid at 25° C. and spindle LV1=390 cPs, DDA=80% (by        colloidal titration).    -   Chitosan B: Primex ChitoClear 43000, TM 4167, MW=110-150 kDa,        Brookfield viscosity in 1.0% w/w chitosan solution in 1.0%        acetic acid at 25° C. and spindle LV1=9 cPs, DDA=95% (by        colloidal titration).    -   Glacial acetic acid: Fisher Scientific, Catalog No. A38-212.    -   Hydrochloric acid: 1.0 M aqueous solution Sigma Aldrich, Catalog        No. H9892.    -   L-Lactic acid: JT Baker, Catalog No. 0196-01.    -   Glycolic acid: JT Baker, Catalog No. M821-05.    -   Sodium hydroxide: 5.0 M NaOH aqueous solution Sigma Aldrich,        Catalog No. S8263-150 ml.    -   Potassium hydroxide: 0.1 M KOH in methanol (BDH).    -   Ethanol: 200° Proof Sigma Aldrich, Catalog No. 459844-1L.    -   Microfiber chitin: ˜10 micron diameter of aspect ratio ˜100/1 of        100% acetylated. Weifang    -   Centrifugal spun chitosan nanofiber Lot G01 of basis weight 12        g/m² Tricol Medical Grade non-woven microfiber.    -   De-ionized water: Ricca ACS Reagent Grade deionized water,        Catalog No. 9152-5.    -   Acetic anhydride: ACS reagent grade obtained from Sigman        Aldrich, Catalog No. 320102-1L.    -   3,4-dihydroxyhydrocinnamic acid (Mw=182.17 g/mo): 98% Sigma        Aldrich, Catalog No. 102601.    -   1-ethyl-3-(-3-dimethylamino-propyl)-carbodiimide: (alternatively        N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride        with common acronym EDC) Sigma Aldrich, Cat. #E7750.    -   Sodium Chloride: Sigma Aldrich, Catalog No. 793566-500g.    -   Synthetic gastric solution: Pepsin—Sigma Aldrich P7000-25G,        NaCl— Sigma Aldrich 793566-500G, H₂O ACS Reagent grade, NaOH—        Sigma Aldrich, Catalog No. 58263-150 ml.    -   Tissue: fresh swine bladder mucosa, fresh swine stomach mucosa        from Animal Biotech Industries Inc.    -   Citrated bovine whole blood: Lampire Biological Laboratory        Bovine CPD, Catalog No. 7720010.    -   Cynaoacrylate: Permabond 910 Tissue Adhesive, Catalog No. 72590.    -   Dialysis Tubing: 3,500 Da MWCO Snakeskin Dialysis Tubing (Fisher        Scientific), Cat. #PI88244.    -   Pectin: MP Biomedicals LLC, Catalog No. 102587.    -   Glycerol: Sigma Aldrich, Catalog No. G-8773.    -   Polyethylene glycol: Spectrum, Catalog No. PO108.    -   Polyethylene oxide: Mw 400,000 da, Sigma Aldrich Catalog No.        372773-500G.    -   Poloxamer 407: Spectrum, Catalog No. P1166.    -   Guar: Sigma Aldrich, Catalog No. G4129.    -   Cellulose (microcrystalline powder): Sigma Aldrich, Catalog No.        435236.    -   Polyacrylic acid: My 1,250,000 Sigma Aldrich, Catalog No.        306215-100G.    -   HemCon Patch® Pro, highly effective commercial chitosan        hemostatic dressings, were used as positive control dressing in        acute hemostatic studies.

Standard surgical gauze was used as a negative control in acutehemostatic studies.

Preparation Of Catechol Chitosan And Characterization Approach 1.

Chitosan A (9.0 g) was dissolved in deionized water (148 g) and HCl (28ml, 1.0 M HCl). A 1:1 (150 ml) solution of water:ethanol was prepared.3,4-dihydroxyhydrocinnamic acid (25.9 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (51.8 mmol)were dissolved in the water/alcohol solution. The water/alcohol solutionwas added to the chitosan solution. The solutions were vigorously mixed.The reaction mixture was controlled to pH 5.4 using dropwise addition of0.1 M HCl and 0.1 NaOH solution and left to react with overhead stirringfor at least 12 hours. Following this, the chitosan solution (˜300 ml)was dialyzed against 5 liters of water acidified with 1 drop of 1.0 MHCl solution for six days and against non-acidified water for at least 3hours. Dialysate was changed at −24 hour intervals throughout theduration of the dialysis with at least 5 changes of water.

Approach 2

Chitosan A (1.5 g) was dissolved in water (140 g) and HCl (5 ml, 1.0MHCl). A 1:1 solution (145 ml) of water: ethanol was prepared.3,4-dihydroxyhydrocinnamic acid (10.5 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (13.0 mmol)were dissolved in the water/alcohol solution. The water/alcohol solutionwas slowly added to the chitosan solution and the reaction mixture wasstirred with an overhead mechanical stirrer at low stirrer speed. Thereaction mixture was controlled to pH 5.5 using dropwise addition of 0.1M NaOH and 0.1 M NaOH solution and left to react for ˜12 hours understirring. After the reaction process, the solution was dialyzed asdescribed in approach 1.

Approach 3

Chitosan A (9.0 g) was dissolved in water (126 g) acidified with HCl (30ml, 1.0M). A 1:1 solution (150 ml) of water: ethanol was prepared withN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (31.3 mmol)dissolved in the water/alcohol solution. Following this,3,4-dihydroxyhydrocinnamic acid (15.7 mmol) was dissolved in 15 ml ofwater and this solution was added slowly to the chitosan solution undermoderate overhead mechanically stirring. The water/alcohol solutioncontaining the N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride was slowly added to the chitosan solution and the reactionmixture was stirred with an overhead mechanical stirrer at low stirrerspeed. The reaction mixture was controlled to pH 5.5 using dropwiseaddition of 0.1 M KOH (in methanol solution) and 0.1 M HCl solution andleft to react for ˜12 hours under stirring. After the reaction process,the solution was dialyzed as described in approach 1.

Approach 4

Chitosan A (9.0 g) was dissolved in water (126 g) acidified with HCl (30ml, 1.0M). The solution was then adjusted to near pH 5.1 using 0.1 M HCland 0.1 M NaOH aqueous solution. A 1:1 solution (150 ml) of water:ethanol was prepared with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (31.3 mmol) dissolved in the water/alcohol solution.Following this, 3,4-dihydroxyhydrocinnamic acid (15.7 mmol) wasdissolved in 15 ml of water and this solution was added slowly to thechitosan solution under moderate overhead mechanically stirring. Thewater/alcohol solution containing theN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride was slowlyadded to the chitosan solution and the reaction mixture was stirred withan overhead mechanical stirrer at low stirrer speed. The reactionmixture was controlled to pH 5.0 using dropwise addition of 0.1 M KOH(in methanol solution) and 0.1 M HCl solution and left to react for ˜12hours under stirring. After the reaction process, the solution wasdialyzed as described in approach 1.

Degree of Substitution of Catechol Chitosan

Quartz UV test cells, 1 cm path length, ×2 (HACH Co., cat #48228-00)were used in acquiring UV/vis spectra. The UV/Vis spectrophotometer wasa Varian Cary Bio 100.

Standard solutions of 3,4-dihydroxyhydrocinnamic acid were prepared inwater and absorbance at 280 nm was plotted against concentration. Theextinction coefficient □ in the Beer Lambert relationship shown belowfor absorbance in dilute solution

A=ε·c·l

A is absorbance (dimensionless) and l is the path length

(Absorbance<0.5) was determined as 2,540±50 liter/(mol·cm). This valuewas used to determine degree of substitution in the modified chitosan indilute aqueous solution of known mass of modified chitosan, known volumeof solution and measured peak absorbance at 280 nm.

The chitosan catechol solution is diluted so that its absorbance at 280nm is less than 0.5 (usually about 1:50 or 1:100). The absorbance, theweight of the solution used in the dilution, and the percent solids(CS-catechol) were used to find the fractional degree of substitution(f_(Ds)) of the HCA with respect to free amines on the chitosan backboneaccording to the equations:-

$f_{DS} = \frac{n_{HCA}}{f_{DDA} \cdot n_{{total}{Chitosan}{mers}}}$$f_{DS} = \frac{A \cdot V \cdot \left\{ {\left( {f_{DDa} \cdot 161} \right) + \left( {1 - {f_{DDA} \cdot 203}} \right)} \right\}}{\varepsilon \cdot l \cdot \left\{ {m_{cc} - \left( {\frac{A \cdot V}{\varepsilon \cdot l} \cdot 165.17} \right)} \right\} \cdot f_{DDA}}$

where A is UV/vis absorbance at 280 nm of the modified chitosan; V isthe volume (liters) of the modified chitosan solution taken to dry toconstant dry mass; mcc is the measured dry mass (g) of the catecholmodified chitosan; f_(DDA) is the fractional degree of deacetylation ofthe chitosan.

Results

The chitosan-catechol syntheses yielded 50-300 mL of chitosan catecholsolution that ranged from milky to clear, light pink to brown, and withviscosity ranging from thin liquid consistency (e.g. water near 1 cpsviscosity) to thick liquid consistency (e.g. honey: viscosity>100,000cps). The synthetic results (see Table 1) were dependent on the initialconcentration of chitosan, avoidance of precipitation of chitosan in thepH adjustment step from near pH 2 to pH 5, maintenance of pH near 5.0 to5.5 during reaction, and thorough removal of low molecular weightcomponents in the dialysis washing step.

TABLE 1 Summary of Characterization Results Cs-Cat Approach PercentSolids (w/w)^(¶) Percent Substitution 1 0.72 ± 0.1 17.2 ± 2 2 0.42 ± 0.1132* 3 concentrated† 0.63 ± 0.1 29.0 ± 3 4 concentrated† 1.80 ± 0.1 26.4± 3 ^(¶)Percentage dry solid in the solution was determinedgravimetrically *Synthesis in approach 2 resulted in excessive Uv/visabsorbance in determination of degree of substitution †Catechol chitosanwas concentrated by heat assisted drying removal of water from thesolution suspended within its dialysis membrane.

Example 2 Freeze Phase Separated Hydrophilic Polymer Dressings

Hydrophilic polymer aqueous solutions were prepared inside 500 ml, 1000ml or 2000 ml Nalgene LDPE bottles or polypropylene beakers by additionof components including, but not limited to, pre-prepared solution,hydrophilic polymer, water, acid, and additional components. FIGS. 8A-8Blist formulation approaches, hydrophilic polymers, and % w/w of solutionhydrophilic polymer components. Some of the formulations in FIGS. 8A-8Bdo not contain chitosan. Formulation strategies are listed in FIGS.8A-8B as A, B, C, D, E, F, and G. Strategy A was primarily as a controlof materials such as chitosan which were expected not to resistdissolution in the stomach as tested by in vitro simulatedgastrointestinal fluid. Reacetylation (Strategy B) was one of theproposed strategies to reduce rate of dissolution/degradation until invitro simulated gastrointestinal fluid testing in the presence of pepsindemonstrated faster rate of degradation and dissolution of chitosan withlower degree of deacetylation. Strategy C was investigation ofcompositions of known polysaccharides (guar, pectin and starch) withoutchitosan which resist in vitro simulated gastrointestinal fluiddigestion. Strategy D was strategy C with chitosan and possibly otherhydrophilic polymers. Strategy E was use of catechol modified chitosanas the only hydrophilic polymer. Strategy F was use of catechol modifiedchitosan with other hydrophilic polymers. Strategy G was use of acentrifugal spun chitosan fiber.

The main problems experienced when formulating for the gastrointestinalhemostatic dressing application were: (1) unexpected and rapid (<10mins) pepsin promoted degradation of chitin and chitosan in syntheticgastric fluid, wherein pepsin promoted a rate of chitosan degradation atincreasing rates corresponding with lower degrees of deacetylation; (2)unexpected interference from blood in achieving adherence with the purecatechol modified chitosans; (3) susceptibility in dressing cracking andtearing when making changes to formulations to address other problems.

The final hydrophilic polymer solution % w/w was between 0.1% to 4%polymer. Capped bottles and their contents were mixed continuously atroom temperature over 12 to 24 hours to achieve full solutionhomogeneity using IKA KS260 orbital shaker or a Wheaton bench top bottleroller. Beaker solutions were mixed on a magnetic stirrer plate withmagnetic stirrer bead at room temperature for 12 to 24 hours to achievesolution homogeneity. Parafilm was used to close the beaker from theexternal environment during mixing. The solutions prepared for freezephase separation were substantially homogeneous and clear whensuspension conditions were not present (exceptions with A06, B02, B04and C05). The catechol chitosan solutions demonstrated some haze andmilky appearance indicating presence of some dispersed fine catecholchitosan globular particles.

Except in the case of Strategy G, chitosan solutions were prepared asfreeze phase separated dressings with final solution % weight ofhydrophilic polymer in the range 0.25% to 4% w/w aqueous solution.Freeze phase separation was performed in Teflon coated aluminum moldwells with horizontal flat bases. The solutions were poured into thewells to a height from the mold base of preferably not more than about10 mm, more preferably 2.5 mm and most preferably 5.0 mm. The solutionsinitially at a temperature in the molds before freezing between 15° C.and 30° C. were then frozen by application of cooling through the baseof the molds. Although other cooling temperatures may be applied toachieve suitable freeze phase separated structure, preferably theapplied cooling temperature of the shelf was −40° C., more preferablythe cooling temperature was −55° C. and most preferably the coolingtemperature was −45° C. After the solution achieved freezing phaseseparation and the temperature of the frozen solution equilibrated atthe freezing temperature, the system was allowed to further freeze phaseseparate and equilibrate for at least an additional hour before drying.In a modified freezing and mold filling method to accommodate layers ofdifferent freeze phase separated solutions, a first layer was added tothe mold to a preferred depth and frozen, a second layer was then addedand frozen, a multi-layered freeze phase separated dressing could beprepared in this manner. Care was needed to ensure there was no frostbetween an (n-1)th frozen and nth poured solution and differences inlayer frozen structure could result in cracking. The discovery of thesuccessful method of layering and adhering of single layer previouslyfreeze dried hydrophilic polymer matrices to a single co-adheredcompressed multilayered composite sheet during this investigation was anunexpected and significant finding. It is also possible to combineseparately prepared freeze dried compositions using compression.

A 24 square foot shelf Virtis Benchmark 2000 pilot scale freeze dryerwas used for sublimation freeze drying of the freeze phase separatedfrozen solution plaques. In the primary freeze drying (removal of icenot hydrogen bonded to the hydrophilic polymers), the equilibratedfrozen plaques in their molds were subjected to reduction in pressure≤300 mTorr within the freeze dryer, the freeze dryer condenser was setto ≤−65° C. and the freeze dryer shelves were heated to promotesublimation of the ice from the freeze separated plaques withoutincreasing plaque temperature above−15° C. After removal ofsubstantially all the non-bonded ice, the shelf temperature was raisedto near 25° C. for removal of the hydrogen bonded ice and reduction ofmoisture content in the dried dressing to not more than about 4%residual water in the dried dressing. Final dried matrices conformed tothe original shape of the filled mold with close to 5% shrinkage inlength and width and density between 0.005 g/cm³ and 0.04 g/cm³. Theycontained void space of more than 95% and they were interconnectedporous structure (e.g., 20-300 micron) with fine polymer lamella (e.g.,submicron to 5 micron thickness) and pore spacing between adjacentlamella of, for example, 20 microns to 300 microns.

After freeze phase separation and drying, the dried matrices werecompressed from their original thicknesses (10 mm to 2.5 mm) to a finalthickness preferably near 50 microns. If two uncompressed dressings werecompressed one on top of the other then they would be permanently bondedtogether at the conclusion of the compression process. Calibrateduniform thickness thin shims may be used in the compression to achieve adesired thickness of compressed dressing substantially the samethickness as the shim. There are a number of ways to achieve thiscompression with a desired compression set near 50 microns. Thepreferred compression method used in the investigation was compressionof the whole dried uncompressed dressing (dimensions typically close to100 mm long×100 mm wide×2.5 mm high or 50 mm diameter×2.5 mm high) withuniaxial compression rate at ≤10 mm/min, or about ≤0.5 mm/min, to ≤100microns thickness between aligned platens. While lower compression rateslead to better mechanical properties of the final dressings, dressingsprepared with initial compression rates near, for example, about 10mm/min are acceptable. The platens (Teflon coated Mic 6 Aluminum 300mm×300 mm×90 mm) were machined to flat planar faces (≤5 microns in 300mm). The temperature of platens during compression was maintainedpreferably near 80° C. over 3 to 5 minutes of uniaxial compression.Compression was achieved by screw loading at the four corners of theplatens at up to four tonnes (tonnes meaning 1000 kilograms) loading ateach corner. Compression was held for at least 2 minutes before releaseof load. The novel compressed hydrophilic polymer matrices were measuredfor compression thickness and weight. Final densities were between 0.35and 0.55 g/cm³. After compression, the dressings were further processed.This additional processing included die cutting into 2.5 cm diametertest pieces and in some cases thermal annealing heat treatment (heatedin a convection oven at 60° C. to 150° C. for 5-30 minutes). At theconclusion of processing the dressings were placed in foil pouches withthermal sealing. Packaged dressings intended for animal andbiocompatibility testing were gamma-irradiated at 25 kGy.

Example 3 In Vitro Testing of Gastrointestinal Hemostatic DressingPrototypes

Synthetic Gastric fluid preparation: Pepsin (1.6 g), NaCl (1 g), water(500 ml) was added to a Nalgene LDPE 1000 ml bottle and mixed. Theacidity was adjusted to be between pH 3 to 4 using Millipore pH 0-14universal indicator strips and dropwise addition of 3.0 M HCl. Dropwiseaddition of 1.0 M NaOH was used to raise the pH if required.

1. Test Tube Method

For rapid screening of test article resistance todissolution/fragmentation in synthetic gastric fluid, a 0.5 cm×0.5 cmpiece of test article sheet was added to the base of a labeled 15 mlFalcon tube and 5 ml of gastric fluid was added to the tube beforecapping and placing upright in an incubator at 37° C. with gentleshaking. The tube was monitored until demonstrabledissolution/fragmentation of the sample was observed and the time todissolution/fragmentation was recorded. The results of test tube testingare provided in FIGS. 6A-6C.

2. Beaker Method

For materials showing resistance in the test tube test, a modified testmethod was developed whereby a 38 mm×38 mm piece of fresh stomach mucosawas adhered inside a polystyrene beaker (250 ml, Fisher Catalog No.08-732-124) at its base using a thin layer of cyanoacrylate adhesiveapplied using a cotton swab. The mucosa surface prior to gluing wasdabbed dry using Texwipe tissue. The adhesive was allowed to dry over2-5 minutes. After becoming fully adhered to the beaker, the top exposedtissue surface was wetted drop-wise (generally 2 drops) with citratedwhole bovine blood, and a 20 mm×20 mm piece from a test article sheetwas adhered to the blood covered mucosa surface by application of 500 gof load applied orthogonally to the mucosa surface for 1 minute througha 25 mm diameter PVC flat head probe. Synthetic gastric fluid at room(˜90 ml) was added to the beaker. Parafilm was used to seal the beakerand the beaker was placed upright on an IKA KS260 orbital shaker in anincubator at 37° C. under mild shaking (130 rpm). The inside of thebeaker was monitored at minutes and then hourly until demonstrableseparation from mucosa and/or dissolution/fragmentation of the samplewas observed and the time to separation/dissolution/fragmentation wasrecorded.

During test method development, the load applied (up to 5 kg) and timeof application for attachment was up to 5 minutes. In comparison tominimally invasive in vivo application the gastrointestinal surgery teamadvised that an application not be more than 300 g load applieduniformly over a 2.5 cm diameter dressing for not more than 30 seconds.The original conditions of 5 kg and 120 seconds were modified to 500 gfor 1 minute. The application of 300 g load for 30 seconds applicationis now applied. Results of beaker testing are provided in FIGS. 6A-6C.

3. Mechanical Fold Testing

Sample sheets were folded 180° along length and width axes and thecrease line was compressed. Dry test sheets (25 mm×25 mm) were foldedand unfolded and observation of resistance to tearing and cracking wasrecorded. Results of fold testing are provided in FIGS. 6A-6C.

4. Mechanical Tissue Adherence

A uniaxial mechanical tester (Instron Model 5844) with 10 N load cellwas used to investigate wet adhesion to mucosa. Adhesion testing wasperformed using ASTM F2258-03 “Standard Test Method for Strength:Properties of Tissue Adhesives in Tension”. Testing was performed with atesting configuration with lower and upper PVC probes uni-axiallyaligned in the z vertical direction so that the edges of their x-yhorizontal, 15.2 mm diameter faces would accurately (±0.2 mm) coincidewith each other with uniaxial lowering of the top probe which wassupported on the upper, movable Instron crosshead in chuck fixture. Thelower PVC probe was supported in a stationary, bottom, chuck fixture.The bottom PVC horizontal surface was used to support a 10 mm×10 mmmucosal tissue sample adhered at least 5 minutes before testing bycyanoacrylate glue to the PVC surface. The top PVC horizontal surfacewas used to support a 10 mm×10 mm CGHD test piece that was adhered by a3M double side tape at least 5 minutes before testing. The square tissuepiece was wetted with 0.25 5 ml of the de-citrated bovine whole bloodCPD prior to lowering the probe onto the test surface. The probe waslowered at 10 mm/min until a maximum load of 0.98 N was reached. Atcontact, the test and tissue pieces contacted accurately (±0.2 mm) andwere mutually co-planar. The uniaxial probe load at 0.98 N wasmaintained for 30 seconds after which the probe was removed at 10 mm/minand maximum failure stress was recorded. The results of adherencetesting are shown in Table 2.

TABLE 2 Probe Adherence Results G01 - F11 - 25% CS-cat, 22-1 PVC ProbeNanospun CS conc'd/2% CS AcOH (No Dressing) (6-layer) (kPa) soln (kPa)(kPa) 1 0.86 2.07 0.30 2 1.47 3.53 0.26 3 2.13 4.46 0.08 4 1.82 6.820.25 5 0.92 3.69 Mean 1.44 4.11 0.22 Std. Dev. 0.55 1.74 0.10

Example 4 In Vivo (Swine Model of Upper Gastrointestinal Bleeding)Screening Study Animals

A total of 4 crossbred adult domestic swine, body weight from 40 to 50kilograms, were used in this study.

All experiments were performed in accordance with the 2011 NationalResearch Council, “Guide for the Care and Use of Laboratory Animal” andapplicable federal regulations. The protocol for the animal is inaccordance with the NIH Guidelines for the Care and Use of LaboratoryAnimals and was approved by the Institutional Animal Care and UseCommittee. All procedures and care of the animals were performed at theapproved animal research facility.

Veterinary staff inspected all of the animals to ensure baseline health.Animals were removed from all bedding 72 hours prior to the procedureand not permitted food 24 hours prior to surgery. Animals were allowedto drink water ad libitum. Twenty minutes prior to the procedure, theanimals were given 500 mg of intravenous Cefotetan and a 250 ml fluidbolus of Ringer's Lactate. After premedication with glycopyrrolate and acombination of tiletamine HCl and zolazepam HCl (Telazol®, Fort DodgeLaboratories, Fort Dodge, IA), anesthesia was induced by mask using 5%isoflurane. The swine was intubated, placed on a ventilator, andmaintained with 2-3% isoflurane with endotracheal intubation. The rightfemoral artery was surgically isolated and cannulated with a 6 Frcatheter to facilitate continuous blood pressure monitoring andretrieval of blood for laboratory studies. To induce a state ofcoagulopathy, 5000 units of heparin, was given intravenously (IV). Acontinuous infusion of heparin of 50 units/kg was used during theprocedure to maintain anticoagulation. An activated clotting time (ACT)level was tested after 10 minutes and then every 20 minutes during theprocedure with additional heparin (50% of the original dose, 2500 units)given IV as needed to maintain ACT >250 seconds anticoagulation. ECG,blood pressure, and oxygen saturation were monitored during surgery andrecovery. Vitals including blood pressure, % isoflurane, O2 flow,respiratory rate, heart rate, SpO2, capillary refill time, bloodpressure and mean arterial pressure, and body temperature were recordedevery 15 minutes.

At the completion of the experiment, while under anesthesia, the animalswere euthanized with IV administration of Euthasol (1 mg/10 lbs). Deathwas confirmed by flat-wave ECG and absence of heart beat by stethoscope.

Gastric Bleeding Model

The swine were prepared using Chlorhexadine and draped in a sterilefashion. A midline laparotomy was performed to expose the stomach. A5-cm segment of the gastroepiploic vessels were dissected free from thegastric wall. For each segment, a 1-cm gastrotomy was made adjacent tothe free but intact blood vessels. The artery was then pushed throughthe gastrotomy and positioned so that it is exposed to the gastriclumen. The gastric incision was then closed in a standard manner alongwith the abdominal wall. An upper endoscopy (GIF Type Q180, Olympus) wasperformed to identify the gastric wound site in the stomach. The woundsite and gastric vessels were then located and incised with anendoscopic biopsy forceps to create a pulsatile bleeding.

The chitosan gastrointestinal hemostatic dressings (CGHD) identified inTable 3, below, were applied with manual application by hand. In brief,an approximate 12 cm incision was made on anterior gastric wall toexpose gastric cavity and to apply the CGHD prototype dressing (20 mm×20mm) on the gastric bleeding site. Before dressing application, bleedrate was determined using dry pre-weighed folded gauze sponges to absorbany blood from the wound over a 15 second period and weighed, multiplied×4 to calculate bleed rate (weight of blood) per minute. The CGHDdressing was placed over the wound with a gauze sponge on top. Manualpressure is applied evenly with light pressure near 200-300 g over thepatch for 30 seconds, with a local pressure in the vicinity of 100 g/cm²or near 10 Kpa (assuming application over the center of a 4 cm² patch)(use of units of mass, such as grams, in this and in similar contextsherein, means a pressure corresponding to the weight of the recited massevenly distributed over the area of the patch). At 30 seconds the gauzewas removed and the area was observed for initial hemostasis andfollowed for signs of rebleeding for up to 10 minutes. At completion ofapplication, the CGHD dressing was removed and dressing tissue adherencewas ranked according to an adherence score in accordance to how thedressing adhered to tissue surface using the Adherence Score System(Table 3).

TABLE 3 Adherence Score Score Description 0 No adherence 1 Littleadherence 2 Moderate adherence 3 Moderate to strong adherence 4 Strongadherence

Results

Gastric Vascular Injury Type of Bleed rate Hemostasis Adhesion DressingCode# (g/min) Rate (%) score 4Ch01.Pect D24  8 70% 2 ChCatechol E1 andE2 NA 29% 2.5 0.25Cat1.5Ch F11 NA 63% 2 0.75Cat0.5Ch F12 NA 50% 1.5Nanofiber G01  5 67% 1 12GSM Patch Pro H01 NA 100%  3.5 Gauze H02 13 33%0

Three CGHD family prototypes (D24, F11, and G01) demonstrated goodhemostatic properties in terms of immediate hemostasis and acceptableadhesion scores in the gastric vascular injury model. Slow wound tissueadherence for pure catechol modified chitosan was addressed bycombination of unmodified chitosan with the catechol chitosan. Finalheat treatment of these compressed freeze phase separated dressings for15 minutes to 30 minutes at close to 80° C. resulted in dressings withgood immediate tissue adherence and thus promising hemostaticperformance in rapidly controlling pulsatile hemorrhagicgastrointestinal bleeding with short (30 seconds) low pressureapplications. It is noted that the Patch Pro is not suitable for use inthe gastroscope delivery as it cannot be folded as required and is toothick. Also, the Patch Pro is formed of standard chitosan which isdegraded in about 15 minutes or less in the upper GI.

Example 5 In Vivo (Swine Model of Upper Gastrointestinal Bleeding) 3Hour Study Animals

A total of 4 crossbred adult domestic swine, body weight from 40 to 50kilograms, were used in this study.

Animal preparation, surgical preparations, animal anesthesia and animalsacrifice were the same as presented in Example 4.

Gastric Bleeding Model

The swine are prepared using Chlorhexadine and draped in a sterilefashion. A midline laparotomy was performed to expose the stomach. Two5-cm segment of the gastroepiploic vessels were dissected free from thegastric wall. For each segment, a 1-cm gastrotomy was made adjacent tothe free but intact blood vessels. The artery was then pushed throughthe gastrotomy and positioned so that it is exposed to the gastriclumen. The gastric incision was then closed in a standard manner alongwith the abdominal wall (FIG. 2 ). An approximate 12 cm incision wasmade on anterior gastric wall to expose gastric cavity. The wound siteand gastric vessels were then located and incised with a forceps tocreate a pulsatile bleeding. Before applied, the dressing bleed rate wasdetermined using premeasured folded gauze sponges to absorb any bloodfrom the wound over a 15 second period and weighed, multiplied ×4 tocalculate bleed rate. The CGHD dressing was then placed over the bleedwound with a gauze sponge on top. Manual pressure is applied evenly overthe patch for 30 seconds. At 30 seconds the gauze was removed and thearea was observed for hemostasis initially and for up to 10 minutes.After 10-minutes observation, if achieved hemostasis, the gastricincision was closed in a layer fashion, i.e., wherein the surgeonsutures incised layers together consecutively. Then the abdominal wallwas closed for 3-hours observation. At completion of 3-hoursapplication, an upper endoscopy (GIF Type Q180, Olympus) was performedto identify the wound dressings for a visual examination. Then theincisions of abdomen and stomach were reopened for gross examination ofthe dressings. The CGHD dressings were removed and gave an adhesionscore in accordance to how the dressing adhered to tissue surface usingthe Adherence Score System (Table 3).

At completion of these procedures, the wound sites were re-prepared byremoval of old clots and residual of wound dressing to re-applied secondsets of dressing as described above. Each wound site was used to test 2dressings in this study phase.

Bleed Rate

Metzenbaum scissors were used to make a semi-transected vascular injuryat gastric vessels to create a pulsatile bleeding. Bleed rate wasmeasured with a pre-weighed gauze and recorded in g/min. Bleed rate foreach injury was determined and recorded prior to dressing application.

Test Pieces Were 20 mm×20 mm.

Eight dressings were tested from each type of Nanospun Chitosan (G01)and Chitosan Catechol Blend (F11).

Application of Test Pieces

The 30-second timer was started as the test piece was applied centrallyover the injury and with sufficient pressure from fingers to stopbleeding. One piece of 50 mm×50 mm gauze was folded into two and appliedover the 20 mm×20 mm test piece. Any subsequent pooled blood wassuctioned from the site. After 30 seconds of light digital pressure(near 300 g load), fingers were removed and the test dressing observedfor any sign of bleeding. If bleeding was observed, pressure wasre-applied for 30 seconds. If hemostasis was achieved upon the releaseof the pressure, dressing was observed for 10 minutes. If there is nobleeding recurrence, the stomach wall was closed and observed through GIscope for 3 hours. If there was no bleeding recurrence after 3 hours,the dressing test piece was considered successful. If bleeding recurredwithin 5 minutes, the dressing was removed and a new dressing applied.Up to two reapplications were utilized.

TABLE 4 below summarizes the result of the study. Dressing # of dressingpassed # of Code# 1st app 2nd app 3rd app dressings tested % success F113 1   2* 13 46 G01 0 3** 1* 12 31 *1 dressing from each group had extradressing to stop oozing after 3^(rd) pressure application **1 dressingwas held for extra 30 seconds

Nanospun chitosan dressing (G01) had 4 successful application out of 12dressings applied. While the 25% catechol/75% 2% chitosan dressing (F11)had 6 successful application out of 13 dressings tested. Two deviationswere noted for the dressing applications: one dressing from each grouphad extra dressing to stop oozing that did not stop on swine #4; and oneof nanospun chitosan dressing was held for extra seconds.

On all applications, an endoscope was inserted to evaluate if thedressing was still present and hemostatic. In all cases, all dressingswere confirmed as present, hemostatic and visible through the scope.After more than 3 hours of dressing application, the stomach was openedto allow the injury sites and dressings to be examined. All dressingswere intact. Clot formation was observed on all wounds. It was noted inall cases of initial dressing success that there was no subsequentbleeding observed from the wounds at the 3 hour timepoint.

The final best dressing prototypes identified through testing inExamples 3, 4, and 5 demonstrated prolonged efficacy once they wereadhered under light manual pressure with short duration application holdnecessary for delivery through a standard gastroscope delivery port. Thebest dressings that were developed were amenable in a folded (or furled)configuration to be delivered through a standard diameter 2.8 mmdiameter delivery channel from a standard gastroscope.

All CGHD dressings that achieved successful hemostasis (completecessation of bleeding) in the first 10 minutes of application with nomore than 3×30 second hold applications remained fully hemostaticthrough the 3 hour test period inside the closed porcine stomach.Success was achieved for 31% of g01 prototype applications and for 46%of the f11 prototype applications. The challenging nature of this studymade success near 50% (i.e. F11 prototype) relevant to clinicalapplication especially when it is noted that all initial successfulmucoadhesive applications resulted in 100% success in the longer term.The mixed chitosan and catechol chitosan dressings provide forsubstantial resistance to digestive fluid digestion, are able to befolded/furled into the most complex and compact forms, and provide forgood adhesive properties in conjunction with mixing with unmodifiedchitosan references.

Example 6

Demonstration of Dressing Deployment by Wire Device from Inside a 3.5 mmDiameter Channel

The devices in this example comprise an expandable support that alsoserves as an axis.

Six prototype wire delivery devices of the invention depicted by FIG. 13were prepared. Two thicknesses of nitinol wire were employed with threedevices made using 0.32 mm diameter wire and three devices made using0.24 mm diameter wire. The prototype wire device support body wasacrylic rod 63 mm long and 3.2 mm diameter. The clear plastic sheathtubing was 72 mm long with internal diameter 3.5 mm and outer diameter3.8 mm. Two pairs of nitinol wires (each 117 mm in length) were used foreach device. The wires were set to fixed angles and articulated lengthsin a salt oven in folding fixtures. Each wire was formed to contain two2 mm long rod attachment points; two articulated spring arms, 30 mm long(14), to act in concert as the wire device support axis; two articulated10 mm long dressing support connectors (15); and one base support springstrut 25 mm long (16). The folded wire pairs, oriented 90° to each alongthe wire support axis, were connected and glued to the acrylic supportrod in 4×90° offset, 2 mm deep fines holes at the end of the rod so thatthe connected whole appeared as shown in FIG. 13 c when looking down thewire axis.

An exemplary paper dressing (FIG. 13 d ) was attached by its back-foldedtab attachment points (17) to the extremity wire ends (18) of FIG. 13 cby cyanoacrylate glue. The dressing with wire delivery ends attached wasfolded to appearance of FIGS. 13 e and 13 f (looking down the wire axis)and the whole assembled and folded device was placed easily within thetube sheath of FIG. 13 b with the side-on appearance of the whole closeto that depicted of furled dressing and compacted wire device in thetubing of FIG. 13 b.

Pushing of the compacted wire and furled dressing about 3 cm out of theconfines of the tubing sheath resulted in repeatable, rapid (about 1second) full opening and of the dressing.

Example 7

Demonstration of Dressing Deployment by Wire Device from Inside a 3.5 mmDiameter Channel. Nitinol Wire Delivery Device with Dressing ApplicationCross Struts with Central Loop Wire Connection

Six prototype wire delivery devices of the invention depicted by FIGS.14 a & 14 b were prepared. Two thicknesses of nitinol wire were employedwith three devices made using 0.32 mm diameter wire and three devicesmade using 0.24 mm diameter wire. The prototype wire device support bodywas acrylic rod 63 mm long and 3.2 mm diameter. The clear plastic sheathtubing was 72 mm long with internal diameter 3.5 mm and outer diameter3.8 mm. Two pairs of nitinol wires (each 117 mm in length) were used foreach device. The wires were set to fixed angles and articulated lengthsin a molten salt bath in folding fixtures. Each wire was formed tocontain two single wire width rod attachment points; two articulatedspring arms, 30 mm long (14), to act in concert as the wire devicesupport axis; two articulated 10 mm long dressing support connectors(15); and one base support spring strut 25 mm long (16) with centralsmall diameter (1.5 mm diameter) 360° coil for fixing the strutstogether centrally to remove possibility of slippage. The folded wirepairs, oriented 90° to each along the wire support axis, were connected(central strut coils intertwined) and glued to the acrylic support rodin 4×90° offset, 2 mm deep fines holes at the end of the rod so that theconnected whole appeared as shown in FIG. 13 b when looking down thewire axis.

A 2.5 cm diameter catechol chitosan dressing was attached by itsback-folded tab attachment points (17) to the extremity wire ends (18)of FIG. 14 b by either of two methods. Direct cyanoacrylate gluing ofthe dressing surface to the nitinol wire strut as used in example 1 wasnot effective in attaching the freeze phase separated, dry, compressedcatechol chitosan dressing because the surface of the chitosan dressingwas not sufficiently strong (<5 g) to hold the load of the attachment.Because of the problem of surface fibrillation/delamination, smallneedle holes (near 500 microns diameter) were made using a sharp needlepoint through the dressing tabs without creation of any tearing orcracking and the edges of the holes were reinforced with amicro-application (by sharp tipped wooden probe) of cyanoacrylate glueon the surfaces of the holes including small areas around the extremityedges of the holes without closing the perforations with cyanoacrylate.After curing of the cyanoacrylate treated catechol chitosan in theholes, the holes demonstrated at least 10× greater strength than thechitosan catechol surface. The reinforced through and through holes werethen used as fiber attachment points to the nitinol wire ends (18) ofthe delivery device with the fiber being tied in a loop around thenitinol wire ends and the fiber glued by cyanoacrylate to the wire toresist any possibility of the fiber loop sliding along the wire. Directcyanoacrylate glue attachment of the nitinol wire ends to thecyanoacrylate reinforced holes was also demonstrated as an option toprovide good local attachment of around 50-100 g to a nitinol end.

The dressing attached by chitosan microfiber looped through thecyanoacrylate reinforced holes to the wire delivery ends of the deviceof FIG. 14 was folded to appearance of FIGS. 13 e and 13 f (looking downthe wire axis) and the whole assembled and folded device was placedwithin the 3.5 mm internal diameter tube sheath with the side-onappearance of the whole close to that depicted of furled dressing andcompacted wire device in the tubing of FIG. 13 b . Pushing of thecompacted wire and furled dressing about 3 cm out of the confines of thetubing sheath resulted in full opening of the catechol chitosan dressingin about 3 seconds.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications, andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet, including U.S. Provisional PatentApplication No. 62/612,000 filed on Dec. 29, 2017, are incorporatedherein by reference, in their entirety.

REFERENCES

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1-35. (canceled)
 36. A gastrointestinal delivery device comprising: anexpandable support; and a dressing in one of a compact condition, atransition condition, and a splayed condition.
 37. The gastrointestinaldelivery device according to claim 36, further comprising an axisconnected to the expandable support.
 38. The gastrointestinal deliverydevice according to claim 36, wherein a single structure comprises theexpandable support and an axis.
 39. The gastrointestinal delivery deviceaccording to claim 36, further comprising a sheath.
 40. Thegastrointestinal delivery device according to claim 36, wherein theexpandable support is in an unexpanded format and the dressing is in acompact condition.
 41. The gastrointestinal delivery device according toclaim 40, wherein the dressing is at least one of compacted, closed,folded, furled, or crimped.
 42. The gastrointestinal delivery deviceaccording to claim 36, wherein the expandable support is in anunexpanded format and the dressing is in a transition condition.
 43. Thegastrointestinal delivery device according to claim 36, wherein theexpandable support is in an expanded format and the dressing is in asplayed condition.
 44. The gastrointestinal delivery device according toclaim 43, wherein the dressing is at least one of spread out, opened,unfolded, unfurled, uncrimped, or expanded.
 45. The gastrointestinaldelivery device according to claim 43, wherein the dressing in thesplayed condition provides a high surface area.
 46. The gastrointestinaldelivery device according to claim 36, wherein the dressing may berepeatedly in one of a compact condition, a transition condition, and asplayed condition.
 47. The gastrointestinal delivery device according toclaim 36, wherein the dressing comprises chitosan.
 48. A method ofdelivering a dressing to a target tissue site in the gastrointestinaltract using the device according to claim 36, comprising: a) fitting theexpandable support and the dressing into a narrow channel, wherein thedressing is in the compact condition; b) expanding the expandablesupport at a target tissue site; c) applying mechanical force to changethe configuration of the dressing from the compact condition to thetransition condition or the splayed condition; d) adhering the dressingto the target tissue site; and e) removing the expandable support fromthe target tissue site.
 49. The method of claim 48, further comprisingadhering the dressing in splayed condition to the target tissue site.50. The method of claim 48, further comprising applying mechanical forceto one or more edges, or the perimeter, of the dressing.
 51. The methodof claim 48, further comprising applying mechanical force to pull thedressing into a splayed condition or to push the dressing into a splayedcondition.
 52. The method of claim 48, wherein the expandable supportfacilitates application of the dressing to the target tissue site. 53.The method of claim 48, wherein the dressing is attached to the deliverydevice by one or more dressing attachment points able to withstand atleast 50 g of load during application of mechanical force to change theconfiguration of the dressing.
 54. The method of claim 48, wherein thedressing is attached to the delivery device by one or more dressingattachment points able to withstand 100 g of load during application ofmechanical force to change the configuration of the dressing.
 55. Amethod of treating gastrointestinal bleeding using the gastrointestinaldelivery device according to claim 36, comprising: a) fitting theexpandable support and the dressing into a narrow channel, wherein thedressing is in the compact condition; b) expanding the expandablesupport at a target tissue site; c) applying mechanical force to changethe configuration of the dressing from the compact condition to thetransition condition or the splayed condition; d) adhering the dressingto the target tissue site; and e) removing the expandable support fromthe target tissue site.